Oxidative Coupling of Amines and Ketones by Combined Vanadium- and

S1

Oxidative Coupling of Amines and Ketones by Combined Vanadium- and Organocatalysis

Abhishek Sud, Devarajulu Sureshkumar and Martin Klussmann

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,

45470 Mülheim an der Ruhr, Germany. email: [email protected]

Supporting Information

Experimental details S1 Substrates S1 Oxidative coupling - general procedures S2 Products S3 Racemisation studies of 3 S6 NMR-spectra S8 HPLC of rac-3 S21 Supporting references S21

Experimental details Except when indicated otherwise, all reagents and solvents were purchased from commercial sources and used as received. All reactions and workup were conducted under air, except when noted otherwise. Flash column chromatography was performed using Merck Silica Gel 60 (0.040-0.063mm). TLC was performed on Macherey Nagel Polygram Sil G/UV254 plates and visualised by UV-light and KMnO4-solution. Yields refer to pure isolated substances. NMR spectra were recorded on a Bruker AV500 MHz spectrometer. The chemical shifts are reported in ppm downfield of internal standard tetramethylsilane for 1H NMR and 13C NMR. Chemical shifts are designated using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Peaks were assigned based on 13C-DEPT- or 2D-NMR spectra or by analogy with derivatives. Mass spectra were recorded on a Finnigan MAT 8200 or a Finnigan SSQ 7000 instrument, high resolution mass determinations were performed on a Bruker APEX III FT-MS or a Finnigan MAT 95 instrument. High performance liquid chromatography (HPLC) was performed on a Shimadzu LC-10A HPLC-system. For preparative HPLC, a Shimadzu LC-8A FRC-10A fraction sampler was used. Racemic samples for determination of the separation conditions were synthesised according to the synthetic procedures described below using racemic proline as the organic cocatalyst.

Substrates The substrates 2-phenyl-1,2,3,4-tetrahydro-isoquinoline (1) and 2-(p-methoxyphenyl)-1,2,3,4-tetrahydro-isoquinoline (4) were synthesized according to literature procedures.S1

Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2009

S2

6,7-Dimethoxy-2-phenyl-1,2,3,4-tetrahydro-isoquinoline (5)

In accordance with a literature procedure.S1 Copper(I) iodide (200 mg, 1.0 mmol) and potas-sium phosphate (4.25 g, 20.0 mmol) were put into a Schlenk tube. The tube was evacuated and refilled with nitrogen. 2-Propanol (10.0 ml), ethylene glycol (1.11 ml, 20.0 mmol), 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (2.9 g, 15 mmol) and iodobenzene (1.12 ml, 10.0 mmol) were added successively. The reaction mixture was stirred at 85-90 °C for 24 h and then allowed to cool to room temperature. Diethyl ether (20 ml) and water (20 ml) were then added to the reaction mixture and the aqueous layer was extracted another two times with diethyl ether (20 ml each). The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was removed by rotary evaporation and purified by column chromatography on silica gel (hexane/ethyl acetate=20:1), giving the product 5 as while solid with 61 % (2.5 g) isolated yield. Rf = 0.60 (EtOAc/pentane, 3 : 7); 1H NMR (500 MHz, CDCl3): δ 7.29 (dd, J = 8.7, 7.4 Hz, 2H), 6.99 (d, J = 5.0 Hz, 2H), 6.83 (t, J = 5.0 Hz, 1H), 6.64 (d, J = 5.0 Hz, 2H), 4.33 (bs, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.55 (t, J = 5.0 Hz, 2H), 2.90 (t, J = 5.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 147.6, 147.5, 129.2, 126.7, 126.2, 118.8, 115.4, 111.3, 109.4, 56.0, 54.7, 55.9, 50.5, 46.8, 28.5; HR - MS m/z: calcd for C17H19NO2[M+]: 269.1416; found: 269.1413.

Oxidative coupling - general procedure A (tetrahydroisoquinolines) The amine (0.12 mmol), VO(acac)2 (0.012 mmol, 10 mol%) and L-proline (0.012 mmol, 10 mol%) are dissolved in 1.0 ml MeOH and acetone (0.60 mmol, 5.0 eq.). A 5.5M solution of tert-butyl hydroperoxide in decane (0.033 ml, 0.18 mmol, 1.5 eq.) is added and the reaction mixture is stirred at room temperature until full conversion of the amine is achieved. Then, water and CH2Cl2 are added and the mixture is extracted with CH2Cl2. The combined organic phases are dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5-10% EtOAc in pentane) gave the corresponding products.

Oxidative coupling - general procedure B (N-methyl pyrrolidines) To a suspension of VO(acac)2 (0.05 mmol, 5 mol%) and L-proline (0.1 mmol, 10 mol%) in 1.0 ml iso-hexane, N-methyl pyrrolidine (1.0 mmol) and ketone (5.0 mmol, 5.0 eq.) were added. A 5.5M solution of tert-butyl hydroperoxide in decane (0.27 ml, 1.5 mmol, 1.5 eq.) was added carefully and the reaction mixture was stirred at room temperature until full conversion of the amine was achieved. The reaction mixture was then filtered over a short pad of silica gel (basified by washing with a solution of 5% NEtMe2 in pentane) which was further washed with CH2Cl2/MeOH. Concentration of the eluted solution in vacuo and purification of the residue by flash column chromatography on basified silica gel (0.5-1% MeOH in CH2Cl2) gave the corresponding products.


S3

Products

1-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (3)

Synthesized according to general procedure A. White solid, rf = 0.50 (EtOAc/pentane, 1 : 9); Yield : 22 mg, 69%; 1H NMR (500 MHz, CDCl3): δ 7.24 (t, J = 8.5 Hz, 2H), 7.18-7.12 (m, 4H), 6.93 (d, J = 8.1 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 3.66-3.62 (m, 1H), 3.56-3.49 (m, 1H), 3.07-3.01 (m, 2H), 2.82 (dd, J = 16.4, 7.0 Hz, 1H), 2.06 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 207.3, 148.8, 138.2, 134.4, 129.3, 128.7, 126.8, 126.3, 118.3, 114.8, 54.8, 50.2, 42.1, 31.1, 27.2; HR - MS m/z: calcd for C18H19NNaO[M++Na]: 288.1364; found: 288.1368. Determination of ee by HPLC: Chiralpak IB (250x4.6mm), n-heptane/2-propanol 97:3, 0.5 ml/min, 25°C, 220nm, rt (3) = 16 min, rt (ent-3) = 33 min (chromatogram: see page S20). Preparative separation of enantiomers by HPLC was performed using a Chiralpak IA column (200x48mm), a mobile phase of iso-hexan/2-propanol (97:3) at 35 ml/min and a temperature of 35°C.

1-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (6)

Synthesized according to general procedure A. Colourless oil, rf = 0.70 (EtOAc/pentane, 1:9); Yield : 22 mg, 65%; 1H NMR (500 MHz, CDCl3): δ 7.25-7.22 (m, 2H), 7.17-7.12 (m, 4H), 6.94 (d, J = 8.2 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 5.41 (t, J = 6.4 Hz, 1H), 3.66-3.61 (m, 1H), 3.56-3.50 (m, 1H), 3.09-3.01 (m, 2H), 2.86-2.75 (m, 2H), 2.39-2.21 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 209.9, 148.8, 138.4, 134.4, 129.3, 128.6, 126.8, 126.7, 118.1, 114.6, 55.1, 48.9, 41.9, 37.3, 27.3, 7.5; HR - MS m/z: calcd for C19H21NNaO[M++Na]: 302.1515; found: 302.1511.

1-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)pentan-2-one (7)

Synthesized according to general procedure A. Colourless oil, rf = 0.70 (EtOAc/pentane, 1:9); Yield : 15 mg, 41%; 1H NMR (500 MHz, CDCl3): δ 7.24 (t, J = 6.2 Hz, 2H), 7.18-7.12 (m, 4H), 6.94 (d, J = 7.0 Hz, 2H), 6.77 (t, J = 6.2 Hz, 1H), 5.43 (t, J = 6.3 Hz, 1H), 3.67-3.62 (m,


S4

1H), 3.56-3.51 (m, 1H), 3.09-3.01 (m, 2H), 2.85-2.75 (m, 2H), 2.34-2.19 (m, 2H), 1.56-1.49 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 209.5, 148.8, 138.4, 134.4, 129.3, 128.6, 126.9, 126.8, 126.2, 118.1, 114.6, 54.9, 49.3, 46.0, 41.9, 27.3, 16.9, 13.6; HR - MS m/z: calcd for C20H23NNaO[M++Na]: 316.1672; found: 316.1669.

4-methyl-1-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)pentan-2-one (8)

Synthesized according to general procedure A. Colourless oil, rf = 0.60 (EtOAc/pentane, 1:9); Yield : 11 mg, 32%; 1H NMR (500 MHz, CDCl3): δ 7.25 (t, J = 6.7 Hz, 2H), 7.15-7.12 (m, 4H), 6.94 (bs, 2H), 6.77 (bs, 1H), 5.44 (t, J = 6.3 Hz, 1H), 3.67-3.62 (m, 1H), 3.56-3.51 (m, 1H), 3.09-3.00 (m, 2H), 2.85-2.74 (m, 2H), 2.23-2.01 (m, 3H), 0.84 (t, J = 3.9 Hz, 3H), 0.83 (t, J = 3.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 209.2, 138.5, 134.4, 129.3, 128.6, 126.9, 126.8, 126.3, 118.1, 114.6, 54.7, 53.0, 49.7, 42.0, 27.3, 24.4, 22.6, 22.5; HR - MS m/z: calcd for C21H25NNaO[M++Na]: 330.1828; found: 330.1825.

1-(2-(p-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (9)

Synthesized according to general procedure A. Colourless oil, rf = 0.50 (EtOAc/pentane, 3:7); Yield : 18 mg, 51%; 1H NMR (500 MHz, CDCl3): δ 7.17-7.09 (m, 4H), 6.91 (bd, J = 8.2 Hz, 2H), 6.81 (d, J = 8.2 Hz, 2H), 5.24 (t, J = 6.4 Hz, 1H), 3.75 (s, 3H), 3.58-3.53 (m, 1H), 3.49-3.43 (m, 1H), 3.03-2.96 (m, 2H), 2.77 (dd, J = 16.1, 6.3 Hz, 1H), 2.72 (bs, 1H), 2.06 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 207.3, 138.3, 134.3, 128.9, 126.8, 126.7, 126.2, 118.4, 114.6, 56.0, 55.6, 49.9, 42.9, 30.9, 26.7; HR - MS m/z: calcd for C19H21NNaO2[M++Na]: 318.1464; found: 318.1466.

1-(2-(p-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (10)

Synthesized according to general procedure A. Colourless oil, rf = 0.70 (EtOAc/pentane, 3:7); Yield : 15 mg, 40%; 1H NMR (500 MHz, CDCl3): δ 7.16-7.10 (m, 4H), 6.91 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 9.1 Hz, 2H), 5.27 (t, J = 6.2 Hz, 1H), 3.75 (s, 3H), 3.58-3.44 (m, 2H), 3.05-2.98 (m, 2H), 2.75-2.71 (m, 2H), 2.36-2.23 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (125


S5

MHz, CDCl3): δ 210.1, 153.1, 143.7, 138.4, 134.3, 128.9, 126.8, 126.6, 126.2, 118.1, 114.7, 56.1, 55.6, 48.7, 42.7, 37.1, 26.8, 7.5; HR - MS m/z: calcd for C20H23NNaO2[M++Na]: 332.1621; found: 332.1624.

1-(6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (11)

Synthesized according to general procedure A. Colourless oil, rf = 0.30 (EtOAc/pentane, 3:7); Yield : 24 mg, 61%; 1H NMR (500 MHz, CDCl3): δ 7.24 (t, J = 8.4 Hz, 2H), 6.94 (d, J = 6.5 Hz, 2H), 6.79 (t, J = 6.5 Hz, 1H), 6.69 (s, 1H), 6.61 (s, 1H), 5.30 (t, J = 6.3 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.69-3.64 (m, 1H), 3.52-3.47 (m, 1H), 3.06-2.94 (m, 2H), 2.83 (dd, J = 16.3, 6.9 Hz, 1H), 2.72-2.69 (m, 1H), 2.09 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 207.7, 149.0, 147.8, 147.4, 130.2, 129.3, 126.3, 118.4, 115.1, 111.3, 109.8, 55.9, 55.8, 54.6, 50.2, 41.9, 31.2, 26.6; HR - MS m/z: calcd for C20H23NO3[M+]: 325.1678; found: 325.1675.

1-(6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (12)

Synthesized according to general procedure A. Colourless oil, rf = 0.40 (EtOAc/pentane, 3:7); Yield : 15 mg, 36%; 1H NMR (500 MHz, CDCl3): δ 7.24 (t, J = 7.7 Hz, 2H), 6.95 (d, J = 6.0 Hz, 2H), 6.78 (t, J = 6.0 Hz, 1H), 6.65 (s, 1H), 6.61 (s, 1H), 5.32 (t, J = 6.4 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.68-3.63 (m, 1H), 3.52-3.48 (m, 1H), 3.03-2.95 (m, 2H), 2.79-2.69 (m, 2H), 2.39-2.24 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 147.8, 147.4, 130.5, 129.3, 126.3, 118.3, 114.9, 111.3, 109.7, 55.9, 55.8, 54.9, 48.8, 42.1, 37.4, 26.7, 7.6; HR - MS m/z: calcd for C21H25NNaO3[M++Na]: 362.1727; found: 362.1729.

Hygrine (14)

Synthesized according to general procedure B. Yellowish oil, rf = 0.42 (CH2Cl2/MeOH/conc. NH3 50:50:1); 1H NMR (500 MHz, CDCl3): δ 3.06-3.01 (ddd, J = 2.4 Hz, J = 7.3 Hz, J = 9.6 Hz, 1H, H2), 2.79 (dd, J = 3.8 Hz, J = 16.2 Hz, 1H, H6), 2.56-2.49 (m, 1H, H5), 2.42 (dd, J = 8.8 Hz, J = 16.2 Hz, 1H, H6), 2.30 (s, 3H, H1), 2.21-2.15 (m, 1H, H2), 2.18 (s, 3H, H8), 2.13-2.05 (m, 1H, H4), 1.81-1.66 (m, 2H, H3), 1.45-1.36 (m, 1H, H4); 13C NMR (125


S6

MHz, CDCl3): δ 208.0 (C7), 61.7 (C5), 56.7 (C2), 48.4 (C6), 40.4 (C1), 31.3 (C4), 30.9 (C8), 22.1 (C3); HR – MS (EI) m/z: calcd for C8H15NO[M+]: 141.115363 ; found: 141.115516. Spectroscopic data for the hydrochloric acid salt were identical with those reported in the literature.S2 Enantiomeric excess was determined by 1H-NMR spectroscopy in CDCl3 using 35 mol% (+)-di-O-4-toluoyl-D-tartaric acid monohydrate as a chiral shift reagent and integrating the C1-methyl signals of the enantiomers at ca. 2.62 and 2.66 ppm (also see the NMR spectra below).

2-(1-methylpyrrolidin-2-yl)cyclopentanone (17)

Synthesized according to general procedure B. Yellowish oil, diastereomeric ratio (17:17’) ca. 1.8:1, determined by 1H-NMR spectroscopy; inseparable by column chromatography; rf = 0.4 (CH2Cl2/MeOH/conc. NH3 90:10:1); 1H NMR (500 MHz, CDCl3): δ 3.09-3.03 (m, 1H, H2,2’), 2.75-2.70 (m, ca. 0.4H, H5’), 2.68-2.62 (m, ca. 0.6H, H5), 2.54-2.48 (m, ca. 0.6H, H6), 2.37-1.9 (m, ca. 9H [2.31/2.17 (2s, 3H, H1,1')]), 1.82-1.66 (m, ca. 4.4H), 1.64-1.57 (m, ca. 0.4H, H4’), 1.44-1.36 (m, ca. 0.6H, H4); 13C NMR (125 MHz, CDCl3): δ 220.9 (C7), 220.4 (C7’), 64.9 (C5), 64.4 (C5’), 57.7 (C2’), 56.7 (C2), 52.6 (C6’), 49.9 (C6), 42.0 (C1’), 40.0 (C1), 39.2 (C8), 30.6 (C4’), 25.5 (C4), 24.5, 23.5, 22.6, 22.2, 20.80, 20.77; HR – MS (EI) m/z: calcd for C10H17NO[M+]: 167.131014 ; found: 167.130846.

2-(1-methylpyrrolidin-2-yl)cyclohexanone (18)

Synthesized according to general procedure B. Yellowish oil, diastereomeric ratio (18:18’) ca. 2.8:1, determined by 1H-NMR spectroscopy; inseparable by column chromatography; rf = 0.3 (CH2Cl2/MeOH/conc. NH3 90:10:1); 1H NMR (500 MHz, CDCl3): δ 3.06-2.99 (m, 1H, H2,2’), 2.75-2.70 (m, ca. 0.3H, H5’), 2.70-2.65 (m, ca. 0.7H, H5), 2.59-2.53 (m, ca. 0.7H, H6), 2.42-2.21 (m, ca. 6H [2.31/2.24 (2s, 3H, H1’, 1)]), 2.19-2.12 (m, ca. 1.3H), 2.08-1.89 (m, ca. 3H), 1.77-1.42 (m, ca. 6H); 13C NMR (125 MHz, CDCl3): δ 212.74 (C7), 212.70 (C7’), 64.0 (C5), 63.6 (C5’), 58.0 (C2’), 57.0 (C2), 56.1 (C6’), 51.7 (C6), 43.5 (C1’), 42.7 (C8’), 42.5 (C8), 40.7 (C1), 30.9, 30.2, 27.9, 27.3, 26.6, 26.5, 25.1, 24.9, 23.6, 23.0; HR – MS (EI) m/z: calcd for C11H19NO[M+]: 181.146665; found: 181.146512.

Racemisation of 3 under reaction conditions Isolated samples of basically enantiopure 3 (by preparative HPLC) were subjected to the reaction conditions of its synthesis, except that no substrate amine 1 was added. Aliquots for analysis were taken after certain time intervals and worked up by addition to a mixture of water and CH2Cl2 and extracting it with CH2Cl2. The combined organic phases are dried over MgSO4, concentrated in vacuo and directly analysed for ee by HPLC:


S7

t % ee 0 99 15h 89 2d 85 3d 83 No further racemisation of the isolated samples occurred after keeping them at room temperature for two days.


S8

NMR-spectra

Compound 3: 1H-NMR – CDCl3 (500 MHz)

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.

00

2.

06

2.

79

2.

81

2.

83

2.

84

3.

01

3.

02

3.

03

3.

03

3.

04

3.

06

3.

06

3.

07

3.

07

3.

50

3.

51

3.

52

3.

52

3.

53

3.

54

3.

55

3.

56

3.

62

3.

63

3.

64

3.

65

3.

66

4.

41

5.

38

5.

40

5.

41

6.

76

6.

77

6.

79

6.

93

6.

94

7.

12

7.

13

7.

14

7.

15

7.

17

7.

17

7.

18

2.91

1.98

2.04

1.03

1.00

1.00

0.93

1.96

3.92

2.06

kum-ka-179-60

Compound 3: 13C-NMR – CDCl3 (125 MHz)

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

0.

00

27

.1

8

31

.0

8

42

.0

7

50

.1

8

54

.8

0

76

.7

87

7.

03

77

.2

9

11

4.

78

11

8.

28

12

6.

28

12

6.

81

12

6.

84

12

8.

67

12

9.

35

13

4.

41

13

8.

25

14

8.

83

20

7.

26kum-ka-179-60

NPh

O


S9


7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.

00

2.

89

2.

90

2.

91

3.

54

3.

55

3.

56

3.

86

3.

87

4.

33

6.

64

6.

65

6.

82

6.

83

6.

84

6.

98

6.

99

7.

25

7.

26

7.

27

7.

27

7.

28

7.

29

7.

30

7.

30

2.05

2.06

6.08

2.06

2.02

1.00

2.03

2.41

kum-ka-403-02


150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

0.

00

28

.5

2

46

.7

7

50

.5

3

55

.9

45

5.

98

76

.7

77

7.

02

77

.2

8

10

9.

37

11

1.

34

11

5.

36

11

8.

79

12

6.

17

12

6.

65

12

9.

18

14

7.

49

14

7.

59

15

0.

69kum-ka-403-02

N

MeO

MeO


S10


7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.

00

0.

96

0.

97

0.

99

1.

60

2.

21

2.

23

2.

24

2.

25

2.

25

2.

26

2.

28

2.

29

2.

31

2.

32

2.

34

2.

34

2.

35

2.

36

2.

37

2.

39

2.

75

2.

77

2.

78

2.

80

2.

81

2.

82

2.

84

2.

85

2.

86

3.

01

3.

02

3.

03

3.

04

3.

04

3.

05

3.

07

3.

08

3.

09

3.

50

3.

51

3.

52

3.

53

3.

54

3.

55

3.

56

3.

61

3.

62

3.

64

3.

65

3.

66

5.

40

5.

41

5.

43

6.

75

6.

76

6.

78

6.

93

6.

95

7.

12

7.

13

7.

14

7.

14

7.

15

7.

16

7.

17

7.

18

2.96

2.00

2.00

2.01

2.05

1.00

0.98

2.00

3.98

2.17

kum-ka-329-02


210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

0.

00

7.

50

27

.2

6

37

.2

6

41

.9

3

48

.9

4

55

.0

9

76

.7

87

7.

03

77

.2

8

11

4.

59

11

8.

11

12

6.

24

12

6.

77

12

6.

85

12

8.

63

12

9.

33

13

4.

43

13

8.

35

14

8.

83

20

9.

96kum-ka-329-02

NPh

O


S11


7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

-0

.0

10

.7

90

.8

00

.8

20

.8

30

.8

40

.8

51

.4

91

.4

91

.5

01

.5

21

.5

31

.5

51

.5

61

.5

91

.6

12

.1

92

.2

12

.2

22

.2

22

.2

32

.2

42

.2

62

.2

82

.2

92

.3

12

.3

12

.3

22

.3

42

.7

52

.7

72

.7

92

.8

02

.8

22

.8

53

.0

13

.0

23

.0

33

.0

43

.0

53

.0

63

.0

73

.0

83

.0

93

.5

13

.5

23

.5

33

.5

33

.5

43

.5

53

.5

63

.6

23

.6

33

.6

43

.6

63

.6

7

5.

41

5.

43

5.

44

6.

76

6.

77

6.

78

6.

88

6.

90

6.

94

6.

95

7.

12

7.

14

7.

14

7.

15

7.

16

7.

16

7.

17

7.

18

2.97

3.17

1.99

1.94

1.99

1.99

1.00

0.94

1.87

3.95

2.53

kum-ka-331-02


210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

0.

00

13

.6

41

6.

93

27

.3

1

41

.9

6

46

.0

14

9.

27

54

.9

0

76

.7

77

7.

02

77

.2

7

11

4.

58

11

8.

09

12

6.

24

12

6.

76

12

6.

89

12

8.

62

12

9.

33

13

4.

43

13

8.

44

14

8.

84

20

9.

54kum-ka-331-02

NPh

nPr

O


S12


7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.

00

0.

83

0.

83

0.

84

0.

85

1.

56

2.

01

2.

03

2.

04

2.

05

2.

05

2.

07

2.

08

2.

09

2.

11

2.

12

2.

13

2.

15

2.

16

2.

19

2.

20

2.

22

2.

23

2.

74

2.

76

2.

78

2.

79

2.

82

2.

85

3.

00

3.

03

3.

04

3.

04

3.

06

3.

07

3.

07

3.

09

3.

53

3.

55

3.

62

3.

63

3.

64

3.

66

3.

67

5.

42

5.

44

5.

45

6.

77

6.

94

7.

12

7.

14

7.

15

7.

23

7.

25

7.

26

7.

27

6.12

3.11

3.95

1.99

1.00

0.98

1.97

4.24

3.56

kum-ka-337-02


210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

0.

00

22

.5

12

2.

54

24

.3

82

7.

31

42

.0

1

49

.7

35

3.

05

54

.7

0

76

.7

67

7.

02

77

.2

7

11

4.

57

11

8.

07

12

6.

25

12

6.

76

12

6.

91

12

8.

61

12

9.

34

13

4.

40

13

8.

51

20

9.

21kum-ka-337-02

NP h

O


S13


7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.

00

2.

06

2.

72

2.

74

2.

76

2.

78

2.

79

2.

96

2.

98

2.

98

3.

00

3.

01

3.

02

3.

03

3.

43

3.

44

3.

46

3.

47

3.

48

3.

49

3.

53

3.

54

3.

54

3.

55

3.

56

3.

57

3.

57

3.

58

3.

75

5.

23

5.

24

5.

26

6.

80

6.

82

6.

91

6.

92

7.

10

7.

11

7.

12

7.

13

7.

15

7.

15

2.97

2.02

2.00

2.08

3.05

1.00

2.05

1.90

3.98

kum-ka-423--02


200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

0.

00

26

.7

2

30

.8

8

42

.9

2

49

.9

5

55

.6

15

6.

01

76

.7

87

7.

03

77

.2

8

11

4.

64

11

8.

44

12

6.

21

12

6.

65

12

6.

80

12

8.

95

13

4.

30

13

8.

25

20

7.

39kum-ka-423--02

N

OMeO


S14


7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.

00

0.

96

0.

97

0.

99

1.

57

2.

23

2.

25

2.

26

2.

27

2.

28

2.

30

2.

31

2.

33

2.

34

2.

35

2.

36

2.

71

2.

72

2.

74

2.

75

2.

98

3.

00

3.

00

3.

02

3.

03

3.

04

3.

05

3.

44

3.

46

3.

48

3.

54

3.

55

3.

56

3.

56

3.

57

3.

58

3.

75

5.

26

5.

27

5.

29

6.

80

6.

82

6.

90

6.

92

7.

10

7.

11

7.

12

7.

13

7.

14

7.

15

7.

16

3.00

2.01

1.98

2.03

2.12

3.11

1.00

2.05

1.92

4.07

0.69

kum-ka-431-02


210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

0.

00

7.

54

26

.8

4

37

.0

6

42

.6

6

48

.7

0

55

.6

45

6.

19

76

.7

77

7.

02

77

.2

7

11

4.

65

11

8.

11

12

6.

15

12

6.

61

12

6.

83

12

8.

90

13

4.

30

13

8.

39

14

3.

67

15

3.

14

21

0.

07kum-ka-431-22

N

OMeO


S15


7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.

00

2.

09

2.

69

2.

72

2.

80

2.

81

2.

83

2.

84

2.

94

2.

95

2.

96

2.

97

2.

98

2.

99

3.

00

3.

03

3.

06

3.

47

3.

48

3.

50

3.

51

3.

52

3.

52

3.

64

3.

65

3.

66

3.

67

3.

68

3.

69

3.

69

3.

70

3.

84

3.

85

5.

29

5.

30

5.

32

6.

61

6.

69

6.

77

6.

79

6.

80

6.

93

6.

95

7.

23

7.

24

7.

26

2.93

1.99

1.96

1.00

1.06

6.07

1.00

0.99

1.00

0.95

1.89

2.33

kum-ka-427-02


200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

0.

00

26

.5

9

31

.1

9

42

.0

0

50

.1

45

4.

60

55

.8

85

5.

99

76

.7

87

7.

04

77

.2

9

10

9.

74

11

1.

33

11

5.

16

11

8.

48

12

6.

26

12

9.

34

13

0.

15

14

7.

42

14

7.

81

14

9.

00

20

7.

69kum-ka-427-02

NPh

O

MeO

MeO


S16


7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

0.

00

0.

97

0.

99

1.

00

1.

57

2.

24

2.

26

2.

27

2.

28

2.

29

2.

31

2.

32

2.

33

2.

35

2.

36

2.

38

2.

38

2.

40

2.

70

2.

71

2.

74

2.

75

2.

77

2.

79

2.

80

2.

95

2.

96

2.

97

2.

98

3.

00

3.

00

3.

01

3.

03

3.

48

3.

50

3.

52

3.

63

3.

64

3.

65

3.

66

3.

66

3.

67

3.

68

3.

83

3.

85

5.

31

5.

32

5.

33

6.

61

6.

65

6.

76

6.

78

6.

79

6.

94

6.

95

7.

23

7.

24

7.

26

3.02

2.05

2.10

2.05

1.08

1.20

6.42

1.00

1.02

1.03

0.96

1.97

2.96

kum-ka-433-02


150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

0.

00

7.

57

26

.6

5

37

.4

0

48

.8

0

54

.9

95

5.

88

55

.9

8

76

.7

77

7.

02

77

.2

8

10

9.

68

11

1.

29

11

4.

99

11

8.

33

12

6.

25

12

9.

35

14

7.

41

14

7.

79kum-ka-433-02

NPh

O

MeO

MeO


S17


14


14


S18

Determination of enantiomeric purity of 14 by 1H-NMR Using (+)-di-O-4-toluoyl-D-tartaric acid monohydrate (DTTA) as a chiral shift reagent in CDCl3.

0%

6,6%

12,5%

24,5%

36,0%

56,6%

DTTAmol% *

*

*

*

*

*

Figure 1: Shift of hygrine peaks upon addition of different amount of DTTA; taken with a racemic sample of 14 in CDCl3. An asterisk denotes the methyl group signals of 14 used to determine the enantiomeric ratio.


S19


17

3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6


17

60 50 40 30


S20


3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6

18


65 60 55 50 45 40 35 30 25

18


S21

HPLC of rac-3 250 mm Chiralpak IB 4.6 mm i.D. n-Heptan/2-Propanol = 97:3, 0.5 ml/min, 2.8 MPa, 298 K UV, 220 nm

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 min-25

0

25

50

75

100

125

150

175

200

225

250

275

300

325

350

375

400

425

450

475

500

525

550

575

mAUDetector A:220nm

Supporting references S1 Z. Li and C.-J. Li, J. Am. Chem. Soc., 2005, 127, 6968. S2 J.-H. Lee, B.-S. Jeong, J.-M. Goo, S.-S. Jew and H.-G. Park, J. Org. Chem., 2006, 71,

6690.


Oxidative Coupling of Amines and Ketones by Combined Vanadium- and

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Transcript of Oxidative Coupling of Amines and Ketones by Combined Vanadium- and