synthesis of (s)-(+)-cericlamine through lipase … of (s)-(+)-cericlamine through lipase-catalyzed...

1

Synthesis of (S)-(+)-cericlamine through lipase-catalyzed

aminolysis of azo acetates

Agnes Prechter, Harald Gröger and Markus R. Heinrich*

Contents 1. General remarks ..................................................................................................... ………4

2. Syntheses ............................................................................................................................ 4

2.1 General procedure for the preparation of racemic azo acetates 7 and alcohols 8 .......... 4

2.2 Compounds ..................................................................................................................... 5

2.2.1 Acetic acid 3-(4-methoxyphenyl)-2-(4-methoxyphenylazo)-2-methyl-

propyl ester (7a) ................................................................................................... 5

2.2.2 3-(4-Methoxyphenyl)-2-(4-methoxyphenylazo)-2-methylpropan-1-ol (8a) ....... 6

2.2.3 Acetic acid 3-(4-fluorophenyl)-2-(4-fluorophenylazo)-2-methyl-

propyl ester (7b) ................................................................................................... 7

2.2.4 3-(4-Fluorophenyl)-2-(4-fluorophenylazo)-2-methylpropan-1-ol (8b) ................ 8

2.2.5 Acetic acid 3-(3,4-dichlorophenyl)-2-(3,4-dichlorophenylazo)-2-methyl-

propyl ester (7c) ................................................................................................... 9

2.2.6 3-(3,4-Dichlorophenyl)-2-(3,4-dichlorophenylazo)-2-methylpropan-1-ol (8c) . 10

2.2.7 Acetic acid 3-(4-bromophenyl)-2-(4-bromophenylazo)-2-methyl-

propyl ester (7d) ................................................................................................. 11

2.2.8 3-(4-Bromophenyl)-2-(4-bromophenylazo)-2-methylpropan-1-ol (8d) ............ 12

2.2.9 Acetic acid 2-methyl-3-phenyl-2-phenylazopropyl ester (7e) ........................... 13

2.2.10 2-Methyl-3-phenyl-2-phenylazopropan-1-ol (8e) .............................................. 14

2.2.11 Acetic acid 3-(2-methoxyphenyl)-2-(2-methoxyphenylazo)-2-methyl- ................

propyl ester (7f) .................................................................................................. 15

2.2.12 3-(2-Methoxyphenyl)-2-(2-methoxyphenylazo)-2-methylpropan-1-ol (8f) ...... 16

Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012

2

2.2.13 Acetic acid 3-(3-methoxyphenyl)-2-(3-methoxyphenylazo)-2-methyl-

propyl ester (7g) ................................................................................................ 17

2.2.14 3-(3-Methoxyphenyl)-2-(3-methoxyphenylazo)-2-methylpropan-1-ol (8g) ...... 18

2.2.15 Acetic acid 3-(3,4-dimethoxyphenyl)-2-(3,4-dimethoxyphenylazo)-2-methyl-

propyl ester (7h) ................................................................................................. 19

2.2.16 3-(3,4-Dimethoxyphenyl)-2-(3,4-dimethoxyphenylazo)-2-methyl- ......................

propan-1-ol (8h) ................................................................................................. 20

2.2.17 Acetic acid 3-(4-cyanophenyl)-2-(4-cyanophenylazo)-2-methylpropyl ..............

ester (7i) .............................................................................................................. 21

2.2.18 4-((1-(4-Cyanophenyl)-3-hydroxy-2-methylpropan-2-yl)diazenyl)- .....................

benzonitrile (8i) .................................................................................................. 22

2.2.19 Acetic acid 2-methyl-3-(4-nitrophenyl)-2-(4-nitrophenylazo)- .............................

propyl ester (7j) .................................................................................................. 23

2.2.20 2-Methyl-3-(4-nitrophenyl)-2-(4-nitrophenylazo)propan-1-ol (8j) ................... 24

2.2.21 Acetic acid 3-(4-chlorophenyl)-2-(4-chlorophenylazo)-2-methyl-

propyl ester (7k) ................................................................................................. 25

2.2.22 3-(4-Chlorophenyl)-2-(4-chlorophenylazo)-2-methylpropan-1-ol (8k) ............. 26

2.2.23 Acetic acid 3-(4-iodophenyl)-2-(4-iodophenylazo)-2-methyl-

propyl ester (7l) .................................................................................................. 27

2.2.24 3-(4-Iodophenyl)-2-(4-iodophenylazo)-2-methylpropan-1-ol (8l) ..................... 28


propyl ester (7m) ................................................................................................ 29

2.2.26 3-(2-Bromophenyl)-2-(2-bromophenylazo)-2-methylpropan-1-ol (8m) ........... 30


propyl ester (7n) ................................................................................................. 31

2.2.28 3-(3-Bromophenyl)-2-(3-bromophenylazo)-2-methylpropan-1-ol (8n) ............ 32


propyl ester (7o) ................................................................................................. 33


3

2.2.30 3-(2,4-Dichlorophenyl)-2-(2,4-dichlorophenylazo)-2-methyl-

propan-1-ol (8o) ................................................................................................. 34


propyl ester (7p) ................................................................................................ 35

2.2.32 3-(3,5-Dichlorophenyl)-2-(3,5-dichlorophenylazo)-2-methyl-

propan-1-ol (8p) ................................................................................................. 36

2.2.33 2-Amino-3-(3,4-dichlorophenyl)-2-methylpropan-1-ol (9) ............................... 37

2.2.34 3-(3,4-Dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol

(Cericlamine) (10) .............................................................................................. 39

3. Optimization and screening experiments for the enzymatic kinetic resolution .............. 39

3.1 Solvent screening (Table 1) .......................................................................................... 39

3.2 Solvent screening with addition of benzylamine (Table 1) .......................................... 40

3.3 Reaction monitoring by HPLC for azo acetate 7b ...................................................... 40

3.4 Substrate screening I (Table 2) ...................................................................................... 41

3.5 Substrate screening II (Table 3) .................................................................................... 42

3.6 Large-Scale enzymatic kinetic resolution of azo acetate 7c .......................................... 45

4. NMR-Spectra ................................................................................................................... 46

4.1 Formation of N-benzylacetamide in enzymatic aminolysis ......................................... 46

4.2 Compounds ................................................................................................................... 48

5. References ........................................................................................................................ 84


4

1. General remarks

Solvents and reagents were used as received. 2-Methallyl acetate was obtained through

acetylation of 2-methallyl alcohol. Diazonium tetrafluoroborates were prepared by previously

reported procedures.[1] 1H NMR were recorded on 360 and 600 MHz spectrometers using

CDCl3 and C6D6 as solvents referenced to TMS (0 ppm), CHCl3 (7.26 ppm) or C6HD5

(7.15 ppm). Chemical shifts are reported in parts per million (ppm). Coupling constants are in

Hertz (J Hz). The following abbreviations are used for the description of signals: s (singlet), d

(doublet), dd (double doublet), t (triplet), m (multiplet), br (broad). 13C NMR were recorded at

90.6 and 151 MHz in CDCl3 and C6D6 using CDCl3 (77.0 ppm) and C6D6 (128.0 ppm) as

standard. Chemical shifts are given in parts per million (ppm). Mass spectra were recorded

using electron impact (EI). Analytical TLC was carried out on Merck silica gel plates using

short wave (254 nm) UV light to visualise components. Silica gel (Kieselgel 60, 40-63 μm,

Merck) was used for flash column chromatography. Analytical HPLC was carried out using a

Daicel Chiralpak® column IC or a Daicel Chiralpak® column IA.

2. Syntheses

2.1 General procedure for the preparation of racemic azo acetates 7 and

alcohols 8[2]

To a mixture of DMSO/H2O (3 mL, 5:2, v/v, previously degassed with argon) were added

FeSO4·7H2O (3 mmol, 834 mg) and 2-methallyl acetate or 2-methallyl alcohol (6 mmol)

under an argon atmosphere. A solution of diazonium tetrafluoroborate (1 mmol) in a mixture

of DMSO/H2O (1.5 mL, 5:2, v/v, previously degassed with argon) was added dropwise. The

reaction mixture was stirred for 15 minutes, then diluted with water (25 mL) and extracted

with diethyl ether (3 × 25 mL). The combined organic phases were washed with brine (1 ×

50 mL) and dried over sodium sulfate. The solvent was evaporated and the products were

purified by column chromatography.


5

2.2 Compounds

2.2.1 Acetic acid 3-(4-methoxyphenyl)-2-(4-methoxyphenylazo)-2-

methylpropyl ester (7a)[3]

OAcN

N

OMe

MeO

C20H24N2O4M = 356.42 g/mol

Prepared from 4-methoxybenzenediazonium tetrafluoroborate (10.0 mmol, 2.22 g) and 2-

methallyl acetate (60.0 mmol, 6.85 g) according to the general procedure. Purification by

column chromatography (hexane/ethyl acetate = 4:1) gave 7a (3.17 mmol, 1.13 g, 63%) as a

yellow oil.

Rf 0.40 (hexane/ethyl acetate = 4:1)

1H-NMR (600 MHz, C6D6): δ = 1.33 (s, 3 H), 1.65 (s, 3 H), 3.09 (d, J = 13.6 Hz,

1 H), 3.16 (d, J = 13.6 Hz, 1 H), 3.19 (s, 3 H), 3.27 (s, 3 H), 4.57 (d,

J = 11.2 Hz, 1 H), 4.62 (d, J = 11.2 Hz, 1 H), 6.70 (d, J = 8.7 Hz, 2 H), 6.72

(d, J = 9.0 Hz, 2 H), 7.00 (d, J = 8.7 Hz, 2 H), 7.85 (d, J = 9.0 Hz, 2 H).

HPLC (Chiralpak® IC column; hexane/2-propanol = 90:10; 0.8 mL/min, 280 nm):

tR = 9.4 min.

The analytical data is in agreement with literature.[3]


6

2.2.2 3-(4-Methoxyphenyl)-2-(4-methoxyphenylazo)-2-methylpropan-1-ol (8a)[3]

OHN

N

OMe

MeO

C18H22N2O3M = 314.38 g/mol

Prepared from 4-methoxybenzenediazonium tetrafluoroborate (2.00 mmol, 444 mg) and 2-

methallyl alcohol (12.0 mmol, 865 mg) according to the general procedure. Purification by

column chromatography (hexane/ethyl acetate = 3:1) gave 8a (0.44 mmol, 137 mg, 44%) as a

yellow oil.


1H-NMR (360 MHz, CDCl3): δ = 1.22 (s, 3 H), 2.94 (d, J = 13.5 Hz, 1 H), 3.09 (d,

J = 13.5 Hz, 1 H), 3.70-3.78 (m, 2 H), 3.78 (s, 3 H), 3.87 (s, 3 H), 6.81 (d,

J = 8.7 Hz, 2 H), 6.97 (d, J = 9.0 Hz, 2 H), 7.15 (d, J = 8.7 Hz, 2 H), 7.70 (d,

J = 9.0 Hz, 2 H).


tR = 11.5 min, 19.2 min.



7

2.2.3 Acetic acid 3-(4-fluorophenyl)-2-(4-fluorophenylazo)-2-methylpropyl

ester (7b)[2]

Prepared from 4-fluorobenzenediazonium tetrafluoroborate (10.0 mmol, 2.10 g) and 2-


column chromatography (hexane/ethyl acetate = 5:1) gave 7b (3.08 mmol, 1.02 g, 62%) as a

yellow oil.


1H-NMR (600 MHz, CDCl3): δ = 1.24 (s, 3 H), 2.06 (s, 3 H), 3.11 (d, J = 13.7 Hz,

1 H), 3.15 (d, J = 13.7 Hz, 1 H), 4.32 (d, J = 11.2 Hz, 1 H), 4.36 (d,

J = 11.2 Hz, 1 H), 6.92 (dd, JH,F = 8.7 Hz, J = 8.7 Hz, 2 H), 7.04 (dd,

JH,F = 5.4 Hz, J = 8.7 Hz, 2 H), 7.14 (dd, JH,F = 8.4 Hz, J = 8.8 Hz, 2 H),7.68

(dd, JH,F = 5.2 Hz, J = 9.0 Hz, 2 H).


tR = 8.6 min.



8

2.2.4 3-(4-Fluorophenyl)-2-(4-fluorophenylazo)-2-methylpropan-1-ol (8b)[2]

OHN

N

F

F

C16H16F2N2OM = 290.31 g/mol

Prepared from 4-fluorobenzenediazonium tetrafluoroborate (2.00 mmol, 420 mg) and 2-


column chromatography (hexane/ethyl acetate = 3:1) gave 8b (0.66 mmol, 191 mg, 66%) as a

yellow oil.



J = 13.5 Hz, 1 H), 3.72 (d, J = 11.9 Hz, 1 H), 3.79 (d, J = 11.9 Hz, 1 H),

6.95 (dd, JH,F = 8.7 Hz, J = 8.7 Hz, 2 H), 7.13-7.20 (m, 4 H), 7.71 (dd,

JH,F = 5.2 Hz, J = 9.0 Hz, 2 H).


tR = 11.1 min, 12.6 min.



9

2.2.5 Acetic acid 3-(3,4-dichlorophenyl)-2-(3,4-dichlorophenylazo)-2-

methylpropyl ester (7c)

OAcN

N

Cl

Cl

Cl

Cl

C18H16Cl4N2O2M = 434.14 g/mol

Prepared from 3,4-dichlorobenzenediazonium tetrafluoroborate (10.0 mmol, 2.61 g) and 2-


column chromatography (hexane/ethyl acetate = 5:1) gave 7c (3.79 mmol, 1.65 g, 76%) as a

yellow oil.



1 H), 2.80 (d, J = 13.6 Hz, 1 H), 4.25 (d, J = 11.3 Hz, 1 H), 4.30 (d,

J = 11.3 Hz, 1 H), 6.45 (dd, J = 2.0 Hz, J = 8.2 Hz, 1 H), 6.91 (d,

J = 8.2 Hz, 1 H), 6.96-7.00 (m, 2 H), 7.20 (dd, J = 2.3 Hz, J = 8.5 Hz, 1 H),

7.70 (d, J = 2.3 Hz, 1 H).

13C-NMR (151 MHz, C6D6): δ = 19.4 (CH3), 20.2 (CH3), 41.1 (CH2), 67.7 (CH2), 72.9

(Cq), 122.4 (CH), 123.8 (CH), 130.1 (CH), 130.2 (CH), 131.1 (CH), 131.2

(Cq), 132.4 (Cq), 132.9 (CH), 133.9 (Cq), 135.3 (Cq), 136.9 (Cq), 150.7 (Cq),

169.6 (Cq).

MS (EI) m/z (%): 434 (<1) [M+], 261 (35), 259 (55), 201 (51), 199 (80), 175 (51),

173 (83), 165 (11), 164 (26), 163 (14), 161 (22), 159 (30), 149 (10), 47 (52),

145 (82), 129 (24), 128 (10), 124 (11), 109 (15), 83 (16), 45 (11), 44 (100).

HRMS (EI) calcd. for C18H16Cl4N2O2 [M+]: 431.9966, found: 431.9967.


tR = 12.0 min.


10

2.2.6 3-(3,4-Dichlorophenyl)-2-(3,4-dichlorophenylazo)-2-methylpropan-1-ol

(8c)

OHN

N

Cl

Cl

Cl

Cl

C16H14Cl4N2OM = 392.11 g/mol

Prepared from 3,4-dichlorobenzenediazonium tetrafluoroborate (2.00 mmol, 522 mg) and 2-


column chromatography (hexane/ethyl acetate = 2.5:1) gave 8c (0.80 mmol, 312 mg, 80%) as

a yellow oil.



J = 13.4 Hz, 1 H), 3.71 (d, J = 11.8 Hz, 1 H), 3.83 (d, J = 11.8 Hz, 1 H),

7.04 (dd, J = 2.1 Hz, J = 8.2 Hz, 1 H), 7.28-7.37 (m, 2 H), 7.54-7.62 (m,

2 H), 7.76-7.80 (m, 1 H).

13C-NMR (90.6 MHz, CDCl3): δ = 19.5 (CH3), 40.4 (CH2), 66.6 (CH2), 74.4 (Cq),

122.1 (CH), 123.4 (CH), 130.0 (CH), 130.1 (CH), 130.7 (Cq), 130.9 (CH),

132.0 (Cq), 132.6 (CH), 133.6 (Cq), 135.1 (Cq), 137.0 (Cq), 150.3 (Cq).

MS (EI) m/z (%): 392 (<1) [M+], 362 (20), 360 (16), 173 (15), 163 (39), 162 (24),

161 (100), 160 (35), 159 (92), 147 (15), 145 (23), 133 (12), 125 (16), 124

(15), 123 (16), 89 (15), 85 (15), 83 (22).

HRMS (EI) calcd. for C16H14Cl4N2O [M+]: 389.9860, found: 389.9861.


tR = 21.6 min, 23.6 min.


11

2.2.7 Acetic acid 3-(4-bromophenyl)-2-(4-bromophenylazo)-2-methylpropyl

ester (7d)

OAcN

N

Br

Br

C18H18Br2N2O2M = 454.16 g/mol

Prepared from 4-bromobenzenediazonium tetrafluoroborate (10.0 mmol, 2.71 g) and 2-


column chromatography (hexane/ethyl acetate = 5:1) gave 7d (2.99 mmol, 1.36 g, 60%) as a

yellow oil.



1 H), 2.90 (d, J = 13.5 Hz, 1 H), 4.35-4.40 (m, 2 H), 6.61 (d, J = 8.5 Hz,

2 H), 7.14-7.17 (m, 2 H), 7.22 (d, J = 8.8 Hz, 2 H), 7.36 (d, J = 8.8 Hz, 2 H).


(Cq), 121.0 (Cq), 124.1 (2×CH), 125.5 (Cq), 131.4 (2×CH), 132.5 (2×CH),

132.6 (2×CH), 135.7 (Cq), 150.6 (Cq), 169.7 (Cq).

MS (EI) m/z (%): 454 (<1) [M+], 271 (35), 269 (35), 211 (30), 209 (30), 185 (77),

183 (78), 171 (26), 169 (23), 157 (58), 155 (60), 131 (23), 130 (100), 129

(25), 116 (13), 115 (20), 91 (16), 90 (29), 89 (13), 83 (16), 76 (21), 75 (18),

44 (100).

HRMS (EI) calcd. for C18H18Br2N2O2 [M+]: 451.9735, found: 451.9735.


tR = 12.2 min.


12

2.2.8 3-(4-Bromophenyl)-2-(4-bromophenylazo)-2-methylpropan-1-ol (8d)

Prepared from 4-bromobenzenediazonium tetrafluoroborate (2.00 mmol, 542 mg) and 2-


column chromatography (hexane/ethyl acetate = 2:1) gave 8d (0.71 mmol, 292 mg, 71%) as a

dark yellow oil.



J = 13.4 Hz, 1 H), 3.71 (d, J = 11.8 Hz, 1 H), 3.79 (d, J = 11.8 Hz, 1 H),

7.08 (d, J = 8.5 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.56 (d, J = 8.9 Hz, 2 H),

7.61 (d, J = 8.9 Hz, 2 H).


120.5 (Cq), 123.7 (2×CH), 125.3 (Cq), 131.1 (2×CH), 132.3 (2×CH), 132.5

(2×CH), 135.8 (Cq), 150.2 (Cq).

MS (EI) m/z (%): 412 (<1) [M+], 384 (25), 382 (59), 380 (27), 185 (24), 183 (22),

173 (73), 172 (47), 171 (100), 170 (48), 169 (89), 157 (25), 155 (25), 131

(12), 130 (29), 116 (11), 115 (14), 91 (49), 90 (60), 89 (43), 85 (22), 83

(34).

HRMS (EI) calcd. for C16H16Br2N2O [M+]: 409.9630, found: 409.9626.


tR = 20.6 min, 23.8 min.


13

2.2.9 Acetic acid 2-methyl-3-phenyl-2-phenylazopropyl ester (7e)[4]

OAcN

N

C18H20N2O2M = 296.36 g/mol

Prepared from benzenediazonium tetrafluoroborate (10.0 mmol, 1.92 g) and 2-methallyl

acetate (60.0 mmol, 6.85 g) according to the general procedure. Purification by column

chromatography (hexane/ethyl acetate = 5:1) gave 7e (2.05 mmol, 608 mg, 41%) as a yellow

oil.

Rf 0.50 (hexane/diethyl ether = 5:1)

1H-NMR (600 MHz, CDCl3): δ = 1.27 (s, 3 H), 2.05 (s, 3 H), 3.13-3.19 (m, 2 H), 4.36

(d, J = 11.2 Hz, 1 H), 4.39 (d, J = 11.2 Hz, 1 H), 7.10-7.13 (m, 2 H), 7.17-

7.26 (m, 3 H), 7.41-7.48 (m, 3 H), 7.64-7.68 (m, 2 H).


tR = 7.5 min.



14

2.2.10 2-Methyl-3-phenyl-2-phenylazopropan-1-ol (8e)[4]

OHN

N

C16H18N2OM = 254.33 g/mol

Prepared from benzenediazonium tetrafluoroborate (2.00 mmol, 384 mg) and 2-methallyl

alcohol (12.0 mmol, 865 mg) according to the general procedure. Purification by column

chromatography (hexane/ethyl acetate = 3:1) gave 8e (0.54 mmol, 137 mg, 54%) as a yellow

oil.

Rf 0.20 (hexane/diethyl ether = 5:1)

1H-NMR (600 MHz, CDCl3): δ = 1.25 (s, 3 H), 2.61 (br, 1 H), 3.03 (d, J = 13.4 Hz,

1 H), 3.17 (d, J = 13.4 Hz, 1 H), 3.76 (d, J = 11.9 Hz, 1 H), 3.79 (d,

J = 11.9 Hz, 1 H), 7.19-7.30 (m, 5 H), 7.43-7.50 (m, 3 H), 7.67-7.71 (m,

2 H).


tR = 15.1 min, 18.3 min.



15

2.2.11 Acetic acid 3-(2-methoxyphenyl)-2-(2-methoxyphenylazo)-2-methylpropyl

ester (7f)[4]



column chromatography (hexane/ethyl acetate = 3:1) gave 7f (3.34 mmol, 1.19 g, 67%) as a

yellow oil.


1H-NMR (360 MHz, C6D6): δ = 1.45 (s, 3 H), 1.61 (s, 3 H), 3.27 (s, 3 H), 3.30 (d,

J = 13.3 Hz, 1 H), 3.38 (s, 3 H), 3.41 (d, J = 13.3 Hz, 1 H), 4.61 (d,

J = 11.2 Hz, 1 H), 4.81 (d, J = 11.2 Hz, 1 H), 6.50 (dd, J = 0.9 Hz,

J = 8.2 Hz, 1 H), 6.62 (dd, J = 1.2 Hz, J = 8.3 Hz, 1 H), 6.73-6.81 (m, 2 H),

6.99-7.13 (m, 3 H), 7.60 (dd, J = 1.8 Hz, J = 7.9 Hz, 1 H).


tR = 11.6 min.



16

2.2.12 3-(2-Methoxyphenyl)-2-(2-methoxyphenylazo)-2-methylpropan-1-ol

(8f)[4]



column chromatography (hexane/ethyl acetate = 2:1) gave 8f (0.50 mmol, 156 mg, 50%) as

a yellow oil.



J = 13.4 Hz, 1 H), 3.30-3.38 (m, 1 H), 3.72-3.76 (m, 2 H), 3.82 (s, 3 H),

3.94 (s, 3 H), 6.85-6.89 (m, 2 H), 6.96 (ddd, J = 1.1 Hz, J = 7.4 Hz,

J = 7.7 Hz, 1 H), 7.03 (dd, J = 1.1 Hz, J = 8.3 Hz, 1 H), 7.18-7.23 (m, 2 H),

7.31 (dd, J = 1.7 Hz, J = 7.8 Hz, 1 H), 7.39 (ddd, J = 1.7 Hz, J = 7.4 Hz,

J = 8.3 Hz, 1 H).


tR = 15.8 min, 17.0 min.



17

2.2.13 Acetic acid 3-(3-methoxyphenyl)-2-(3-methoxyphenylazo)-2-methylpropyl

ester (7g)[4]

OAcN

N

OMe

OMe

C20H24N2O4M = 356.42 g/mol



column chromatography (hexane/ethyl acetate = 3:1) gave 7g (1.62 mmol, 576 mg, 32%) as a

yellow oil.



1 H), 3.17 (d, J = 13.4 Hz, 1 H), 3.28-3.30 (m, 6 H), 4.53 (d, J = 11.2 Hz,

1 H), 4.57 (d, J = 11.2 Hz, 1 H), 6.67 (ddd, J = 0.9 Hz, J = 2.6 Hz,

J = 8.2 Hz, 1 H), 6.70-6.74 (m, 1 H), 6.74-6.77 (m, 1 H), 6.83 (ddd,

J = 1.0 Hz, J = 2.6 Hz, J = 8.2 Hz, 1 H), 6.98-7.05 (m, 1 H), 7.05-7.11 (m,

1 H), 7.44-7.47 (m, 1 H), 7.50 (ddd, J = 1.0 Hz, J = 1.7 Hz, J = 7.8 Hz,

1 H).


tR = 11.0 min.



18

2.2.14 3-(3-Methoxyphenyl)-2-(3-methoxyphenylazo)-2-methylpropan-1-ol

(8g)[4]

OHN

N

OMe

OMe

C18H22N2O3M = 314.38 g/mol




red oil.



J = 13.3 Hz, 1 H), 3.74 (s, 3 H), 3.78-3.80 (m, 2 H), 3.86 (s, 3 H), 6.74-6.80

(m, 2 H), 6.81-6.85 (m, 1 H), 7.01(ddd, J = 1.3 Hz, J = 2.6 Hz, J = 8.0 Hz,

1 H), 7.15-7.22 (m, 2 H), 7.33 (td, J = 1.4 Hz, J = 7.8 Hz, 1 H), 7.38 (t,

J = 7.9 Hz, 1 H).


tR = 15.8 min, 16.3 min.



19

2.2.15 Acetic acid 3-(3,4-dimethoxyphenyl)-2-(3,4-dimethoxyphenylazo)-2-

methylpropyl ester (7h)[4]

OAcN

N

OMe

OMe

C22H28N2O6M = 416.47 g/mol

OMe

MeO

Prepared from 3,4-dimethoxybenzenediazonium tetrafluoroborate (10.0 mmol, 2.52 g) and 2-


column chromatography (hexane/ethyl acetate = 1:1) gave 7h (3.22 mmol, 1.34 g, 64%) as a

yellow oil.



1 H), 3.24 (d, J = 13.6 Hz, 1 H), 3.30 (s, 3 H), 3.37 (s, 3 H), 3.38 (s, 3 H),

3.39 (s, 3 H), 4.63 (d, J = 11.2 Hz, 1 H), 4.71 (d, J = 11.2 Hz, 1 H), 6.52 (d,

J = 8.4 Hz, 1 H), 6.54 (d, J = 8.1 Hz, 1 H), 6.62 (d, J = 2.0 Hz, 1 H), 6.70

(dd, J = 2.0 Hz, J = 8.1 Hz, 1 H), 7.51 (d, J = 2.2 Hz, 1 H), 7.61 (dd,

J = 2.2 Hz, J = 8.4 Hz, 1 H).

HPLC (Chiralpak® IA column; hexane/2-propanol = 90:10; 0.8 mL/min, 280 nm):

tR = 16.7 min, 19.0 min.



20

2.2.16 3-(3,4-Dimethoxyphenyl)-2-(3,4-dimethoxyphenylazo)-2-methylpropan-1-

ol (8h)[4]

OHN

N

OMe

OMe

OMe

MeO

C20H26N2O5M = 374.43 g/mol

Prepared from 3,4-dimethoxybenzenediazonium tetrafluoroborate (2.00 mmol, 504 mg) and

2-methallyl alcohol (12.0 mmol, 865 mg) according to the general procedure. Purification by

column chromatography (hexane/ethyl acetate = 1:2) gave 8h (0.56 mmol, 211 mg, 56%) as a

dark red solid.



J = 13.5 Hz, 1 H), 3.76 (s, 3 H), 3.76-3.78 (m, 2 H), 3.85 (s, 3 H), 3.94 (s,

3 H), 3.96 (s, 3 H), 6.72-6.74 (m, 1 H), 6.77-6.79 (m, 2 H), 6.95 (d,

J = 8.5 Hz, 1 H), 7.23 (d, J = 2.2 Hz, 1 H), 7.42 (dd, J = 2.2 Hz, J = 8.5 Hz,

1 H).


tR = 34.6 min, 40.2 min.



21

2.2.17 Acetic acid 3-(4-cyanophenyl)-2-(4-cyanophenylazo)-2-methylpropyl

ester (7i)[4]

OAcN

N

CN

NC

C20H18N4O2M = 346.38 g/mol

Prepared from 4-cyanobenzenediazonium tetrafluoroborate (10.0 mmol, 2.17 g) and 2-


column chromatography (hexane/ethyl acetate = 2:1) gave 7i (3.78 mmol, 1.31 g, 76%) as a

yellow oil.



1 H), 2.84 (d, J = 13.4 Hz, 1 H), 4.25 (d, J = 11.4 Hz, 1 H), 4.29 (d,

J = 11.4 Hz, 1 H), 6.57 (d, J = 8.4 Hz, 2 H), 6.93 (d, J = 8.4 Hz, 2 H), 6.99

(d, J = 8.7 Hz, 2 H), 7.25 (d, J = 8.7 Hz, 2 H).


tR = 20.7 min.



22

2.2.18 4-((1-(4-Cyanophenyl)-3-hydroxy-2-methylpropan-2-yl)diazenyl)-

benzonitrile (8i)[4]

OHN

N

CN

NC

C18H16N4OM = 304.35 g/mol

Prepared from 4-cyanobenzenediazonium tetrafluoroborate (2.00 mmol, 434 mg) and 2-


column chromatography (hexane/ethyl acetate = 1:1) gave 8i (0.77 mmol, 233 mg, 77%) as a

yellow solid.


1H-NMR (600 MHz, C6D6): δ = 0.94 (s, 3 H), 1.62 (br, 1 H), 2.77 (d, J = 13.1 Hz,

1 H), 2.89 (d, J = 13.1 Hz, 1 H), 3.40 (d, J = 11.6 Hz, 1 H), 3.54 (d,

J = 11.6 Hz, 1 H), 6.76 (d, J = 8.4 Hz, 2 H), 6.99 (d, J = 8.4 Hz, 2 H), 7.00

(d, J = 8.7 Hz, 2 H), 7.19 (d, J = 8.7 Hz, 2 H).


tR = 29.0 min, 32.0 min.



23

2.2.19 Acetic acid 2-methyl-3-(4-nitrophenyl)-2-(4-nitrophenylazo)propyl ester

(7j)

OAcN

N

NO2

O2N

C18H18N4O6M = 386.36 g/mol

Prepared from 4-nitrobenzenediazonium tetrafluoroborate (1.00 mmol, 237 mg) and 2-

methallyl acetate (6.00 mmol, 685 mg) according to the general procedure. Purification by

column chromatography (hexane/ethyl acetate = 2:1) gave 7j (0.18 mmol, 68.5 mg, 36%) as a

yellow oil.



1 H), 3.39 (d, J = 13.5 Hz, 1 H), 4.35 (d, J = 11.4 Hz, 1 H), 4.44 (d,

J = 11.4 Hz, 1 H), 7.27 (d, J = 8.8 Hz, 2 H), 7.77 (d, J = 9.1 Hz, 2 H), 8.12

(d, J = 8.8 Hz, 2 H), 8.36 (d, J = 9.1 Hz, 2 H).

13C-NMR (151 MHz, CDCl3): δ = 19.9 (CH3), 20.8 (CH3), 41.7 (CH2), 67.4 (CH2),

73.6 (Cq), 122.9 (2×CH), 123.3 (2×CH), 124.8 (2×CH), 131.4 (2×CH),

144.0 (Cq), 147.0 (Cq), 148.9 (Cq), 154.5 (Cq), 170.4 (Cq).

MS (EI) m/z (%): 386 (1) [M+], 237 (19), 236 (100), 194 (39), 176 (14), 164 (10),

151 (12), 150 (72), 131 (11), 130 (93), 129 (18), 122 (57), 115 (14), 83 (11),

76 (13), 75 (11).

HRMS (EI) calcd. for C18H18N4O6 [M+]: 386.1226, found: 386.1226.


tR = 50.9 min, 54.2 min.


24

2.2.20 2-Methyl-3-(4-nitrophenyl)-2-(4-nitrophenylazo)propan-1-ol (8j)

OHN

N

NO2

O2N

C16H16N4O5M = 344.32 g/mol

Prepared from 4-nitrobenzenediazonium tetrafluoroborate (1.00 mmol, 237 mg) and 2-


column chromatography (hexane/ethyl acetate = 1:1) gave 8j (0.13 mmol, 43.5 mg, 26%) as a

dark yellow solid.



J = 13.2 Hz, 1 H), 3.75 (d, J = 11.9 Hz, 1 H), 3.92 (d, J = 11.9 Hz, 1 H),


8.37 (d, J = 9.1 Hz, 2 H).

13C-NMR (151 MHz, CDCl3): δ = 19.6 (CH3), 40.9 (CH2), 66.5 (CH2), 75.4 (Cq),

122.9 (2×CH), 123.3 (2×CH), 124.8 (2×CH), 131.6 (2×CH), 144.6 (Cq),

146.9 (Cq), 149.0 (Cq), 154.4 (Cq).

MS (EI) m/z (%): 344 (2) [M+], 315 (38), 314 (100), 195 (11), 194 (98), 176 (12),

164 (16), 151 (21), 150 (41), 138 (42), 137 (24), 136 (48), 132 (10), 130

(23), 123 (12), 122 (41), 115 (14), 106 (20), 92 (10), 91 (14), 90 (26), 89

(25), 78 (23).

HRMS (EI) calcd. for C16H16N4O5 [M+]: 344.1121, found: 344.1122.


tR = 21.8 min, 22.8 min.


25

2.2.21 Acetic acid 3-(4-chlorophenyl)-2-(4-chlorophenylazo)-2- methylpropyl

ester (7k)

OAcN

NCl

Cl

C18H18Cl2N2O2M = 365.25 g/mol

Prepared from 4-chlorobenzenediazonium tetrafluoroborate (5.00 mmol, 1.13 g) and 2-


column chromatography (hexane/ethyl acetate = 8:1) gave 7f (1.78 mmol, 649 mg, 71%) as a

yellow oil.



1 H), 3.16 (d, J = 13.6 Hz, 1 H), 4.32 (d, J = 11.2 Hz, 1 H), 4.36 (d,

J = 11.2 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 2 H), 7.12 (d, J = 8.5 Hz, 2 H), 7.44

(d, J = 8.8 Hz, 2 H), 7.61 (d, J = 8.8 Hz, 2 H).


72.4 (Cq), 123.5 (2×CH), 128.2 (2×CH), 129.2 (2×CH), 131.9 (2×CH),

132.5 (Cq), 134.9 (Cq), 136.7 (Cq), 150.0 (Cq), 170.7 (Cq).

MS (EI) m/z (%): 365 (<1) [M+], 227 (15), 225 (51), 167 (29), 166 (12), 165 (83),

141 (27), 139 (83), 130 (18), 129 (16), 127 (18), 125 (39), 113 (24), 111

(82), 89 (10), 75 (15), 43 (100).



tR = 11.4 min.


26

2.2.22 3-(4-Chlorophenyl)-2-(4-chlorophenylazo)-2-methylpropan-1-ol (8k)

OHN

NCl

Cl

C16H16Cl2N2OM = 323.22 g/mol

Prepared from 4-chlorobenzenediazonium tetrafluoroborate (1.00 mmol, 226 mg) and 2-


column chromatography (hexane/ethyl acetate = 4:1) gave 8f (0.32 mmol, 104 mg, 64%) as a

yellow oil.



J = 13.4 Hz, 1 H), 3.71 (d, J = 11.9 Hz, 1 H), 3.80 (d, J = 11.9 Hz, 1 H),


7.64 (d, J = 8.8 Hz, 2 H).


123.5 (2×CH), 128.2 (2×CH), 129.3 (2×CH), 132.1 (2×CH), 132.4 (Cq),

135.3 (Cq), 136.9 (Cq), 149.8 (Cq).

MS (EI) m/z (%): 323 (<1) [M+], 294 (32), 292 (49), 139 (12), 129 (21), 128 (22),

127 (100), 126 (54), 125 (93), 111 (20), 99 (21), 90 (11), 89 (22).



tR = 17.2 min, 18.9 min.


27

2.2.23 Acetic acid 3-(4-iodophenyl)-2-(4-iodophenylazo)-2-methylpropyl ester

(7l)

Prepared from 4-iodobenzenediazonium tetrafluoroborate (10.0 mmol, 3.18 g) and 2-


column chromatography (hexane/ethyl acetate = 8:1) gave 7k (3.48 mmol, 1.91 g, 70%) as a

yellow oil.



1 H), 2.88 (d, J = 13.5 Hz, 1 H), 4.31-4-40 (m, 2 H), 6.49 (d, J = 8.4 Hz,

2 H), 7.21 (d, J = 8.7 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.7 Hz,

2 H).

13C-NMR (90.6 MHz, C6D6): δ = 19.5 (CH3), 20.3 (CH3), 41.8 (CH2), 67.9 (CH2),

72.7 (Cq), 92.4 (Cq), 97.6 (Cq), 124.2 (2×CH), 132.9 (2×CH), 136.3 (Cq),

137.4 (2×CH), 138.6 (2×CH), 151.3 (Cq), 169.7 (Cq).

MS (EI) m/z (%): 548 (<1) [M+], 317 (67), 257 (12), 231 (100), 217 (19), 203 (62),

131 (12), 130 (89), 129 (11), 115 (11), 90 (13), 76 (23).

HRMS (EI) calcd. for C18H18I2N2O2 [M+]: 547.9458, found: 547.9457.


tR = 14.1 min.


28

2.2.24 3-(4-Iodophenyl)-2-(4-iodophenylazo)-2-methylpropan-1-ol (8l)

Prepared from 4-iodobenzenediazonium tetrafluoroborate (1.00 mmol, 318 mg) and 2-


column chromatography (hexane/ethyl acetate = 4:1) gave 8k (0.33 mmol, 169 mg, 66%) as a

yellow oil.



J = 13.3 Hz, 1 H), 3.70 (d, J = 11.9 Hz, 1 H), 3.79 (d, J = 11.9 Hz, 1 H),


7.83 (d, J = 8.7 Hz, 2 H).

13C-NMR (151 MHz, CDCl3): δ = 19.6 (CH3), 40.9 (CH2), 66.7 (CH2), 74.0 (Cq), 91.9

(Cq), 97.5 (Cq), 123.8 (2×CH), 132.8 (2×CH), 136.5 (Cq), 137.1 (2×CH),

138.3 (2×CH), 150.8 (Cq).

MS (EI) m/z (%): 506 (<1) [M+], 476 (18), 475 (100), 347 (12), 275 (12), 231 (22),

219 (70), 218 (44), 217 (69), 203 (28), 130 (13), 115 (14), 91 (27), 90 (35),

89 (19), 76 (16).

HRMS (EI) calcd. for C16H16I2N2O [M+]: 505.9353, found: 505.9353.


tR = 24.7 min, 30.9 min.


29


ester (7m)

OAcN

NBr

BrC18H18Br2N2O2

M = 454.16 g/mol




yellow oil.



1 H), 3.51 (d, J = 13.9 Hz, 1 H), 4.44-4.52 (m, 2 H), 7.03-7.09 (m, 1 H),

7.13-7.21 (m, 2 H), 7.25-7.38 (m, 3 H), 7.52-7.57 (m, 1 H), 7.69 (dd,

J = 1.0 Hz, J = 7.8 Hz, 1 H).


74.3 (Cq), 117.9 (CH), 124.1 (Cq), 126.1 (Cq), 127.0 (CH), 128.0 (CH),

128.3 (CH), 131.4 (CH), 132.5 (CH), 133.1 (CH), 133.5 (CH), 136.4 (Cq),

149.1 (Cq), 170.8 (Cq).

MS (EI) m/z (%): 454 (1) [M+], 272 (13), 271 (86), 270 (12), 269 (88), 211 (63), 209

(66), 185 (56), 183 (58), 171 (36), 169 (35), 157 (49), 155 (51), 131 (23),

130 (100), 129 (25), 116 (11), 115 (22), 91 (21), 90 (23), 76 (15), 75 (12).



tR = 13.7 min.


30

2.2.26 3-(2-Bromophenyl)-2-(2-bromophenylazo)-2-methylpropan-1-ol (8m)

OHN

NBr

BrC16H16Br2N2O

M = 412.12 g/mol




yellow oil.



1 H), 3.47 (d, J = 13.8 Hz, 1 H), 3.81-3.87 (m, 2 H), 7.08 (ddd, J = 1.7 Hz,

J = 7.5 Hz, J = 7.9 Hz, 1 H), 7.23 (ddd, J = 1.3 Hz, J = 7.5 Hz, J = 7.6 Hz,

1 H), 7.29-7.41 (m, 4 H), 7.57 (dd, J = 1.3 Hz, J = 8.0 Hz, 1 H), 7.71 (dd,

J = 1.2 Hz, J = 7.9 Hz, 1 H).


117.8 (CH), 124.5 (Cq), 126.1 (Cq), 127.1 (CH), 128.1 (CH), 128.2 (CH),

131.9 (CH), 132.8 (CH), 133.0 (CH), 133.4 (CH), 136.7 (Cq), 148.4 (Cq).

MS (EI) m/z (%): 412 (<1) [M+], 384 (16), 382 (22), 380 (12), 222 (11), 181 (22),

173 (17), 172 (47), 171 (100), 170 (42), 169 (35), 157 (14), 155 (13), 147

(29), 131 (12), 130 (14), 115 (12), 91 (35), 90 (46), 89 (22).



tR = 19.3 min, 20.2 min.


31


ester (7n)

Prepared from 3-bromobenzenediazonium tetrafluoroborate (5.00 mmol, 1.35 g) and 2-


column chromatography (hexane/ethyl acetate = 8:1) gave 7j (1.90 mmol, 861 mg, 76%) as a

yellow oil.



1 H), 3.16 (d, J = 13.6 Hz, 1 H), 4.32 (d, J = 11.3 Hz, 1 H), 4.38 (d,

J = 11.3 Hz, 1 H), 7.00-7.03 (m, 1 H), 7.11 (t, J = 7.8 Hz, 1 H), 7.27 (t,

J = 1.8 Hz, 1 H), 7.33-7.38 (m, 2 H), 7.58 (ddd, J = 1.0 Hz, J = 1.9 Hz,

J = 7.9 Hz, 1 H), 7.62 (ddd, J = 1.0 Hz, J = 1.8 Hz, J = 7.8 Hz, 1 H), 7.78 (t,

J = 1.9 Hz, 1 H).


72.6 (Cq), 122.0 (CH), 122.1 (Cq), 123.0 (Cq), 124.4 (CH), 129.2 (CH),

129.6 (CH), 129.7 (CH), 130.4 (CH), 133.4 (CH), 133.7 (CH), 138.7 (Cq),

152.6 (Cq), 170.7 (Cq).

MS (EI) m/z (%): 454 (<1) [M+], 271 (61), 269 (61), 211 (37), 209 (36), 185 (46),

183 (47), 171 (15), 169 (12), 157 (45), 155 (46), 131 (18), 130 (100), 129

(16), 115 (14), 91 (12), 90 (15), 76 (13).



tR = 11.7 min.


32

2.2.28 3-(3-Bromophenyl)-2-(3-bromophenylazo)-2-methylpropan-1-ol (8n)



column chromatography (hexane/ethyl acetate = 4:1) gave 8j (0.37 mmol, 153 mg, 74%) as a

yellow oil.



1 H), 3.13 (d, J = 13.4 Hz, 1 H), 3.74 (d, J = 11.9 Hz, 1 H), 3.81 (d,

J = 11.9 Hz, 1 H), 7.12-7.17 (m, 2 H), 7.34-7.40 (m, 3 H), 7.59 (ddd,

J = 1.0 Hz, J = 2.0 Hz, J = 7.9 Hz, 1 H), 7.65 (ddd, J = 1.0 Hz, J = 1.9 Hz,

J = 7.9 Hz, 1 H) 7.79-7.82 (m, 1 H).


122.1 (Cq), 122.2 (CH), 123.1 (Cq), 124.2 (CH), 129.4 (CH), 129.5 (CH),

129.6 (CH), 130.5 (CH), 133.6 (CH), 133.7 (CH), 139.2 (Cq), 152.4 (Cq).

MS (EI) m/z (%): 412 (<1) [M+], 384 (40), 383 (14), 382 (82), 380 (43), 229 (14),

227 (13), 211 (13), 210 (11), 185 (15), 183 (15), 173 (72), 172 (52), 171

(100), 170 (48), 169 (80), 157 (21), 155 (21), 132 (12), 131 (17), 130 (32),

116 (11), 115 (13), 91 (52), 90 (58), 89 (33).



tR = 20.4 min, 22.1 min.


33


propyl ester (7o)

OAcN

NCl

Cl

Cl

Cl

C18H16Cl4N2O2M = 434.14 g/mol




yellow oil.



1 H), 3.41 (d, J = 14.0 Hz, 1 H), 4.42 (d, J = 11.3 Hz, 1 H), 4.45 (d,

J = 11.3 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 7.12 (dd, J = 2.2 Hz,

J = 8.3 Hz, 1 H), 7.28 (dd, J = 2.1 Hz, J = 8.6 Hz, 1 H), 7.31 (d, J = 8.6 Hz,

1 H), 7.37 (d, J = 2.2 Hz, 1 H), 7.52 (d, J = 2.1 Hz, 1 H).


74.3 (Cq), 118.5 (CH), 126.7 (CH), 127.7 (CH), 129.5 (CH), 130.3 (CH),

133.1 (Cq), 133.2 (Cq), 133.3 (CH), 135.1 (Cq), 135.8 (Cq), 137.0 (Cq), 146.4

(Cq), 170.6 (Cq).

MS (EI) m/z (%): 434 (<1) [M+], 261 (53), 260 (11), 259 (80), 201 (47), 200 (10),

199 (67), 175 (64), 173 (100), 164 (21), 163 (15), 161 (31), 159 (45), 147

(35), 145 (46), 129 (18), 124 (10), 109 (11).



tR = 8.2 min.


34


(8o)

OHN

NCl

Cl

Cl

Cl

C16H14Cl4N2OM = 392.11 g/mol




yellow oil.



J = 13.7 Hz, 1 H), 3.77 (d, J = 12.3 Hz, 1 H), 3.84 (d, J = 12.3 Hz, 1 H),

7.17 (dd, J = 2.2 Hz, J = 8.3 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 1 H), 7.30 (dd,

J = 2.1 Hz, J = 8.6 Hz, 1 H), 7.36 (d, J = 8.6 Hz, 1 H), 7.39 (d, J = 2.2 Hz,

1 H), 7.55 (d, J = 2.1 Hz, 1 H).


118.2 (CH), 126.8 (CH), 127.9 (CH), 129.4 (CH), 130.2 (CH), 133.1 (Cq),

133.4 (Cq), 133.6 (CH), 135.2 (Cq), 135.8 (Cq), 137.4 (Cq), 145.8 (Cq).

MS (EI) m/z (%): 392 (<1) [M+], 363 (20), 361 (44), 359 (33), 164 (12), 163 (39),

162 (45), 161 (100), 160 (64), 159 (80), 135 (12), 124 (12), 123 (11).



tR = 10.6 min.


35


propyl ester (7p)




yellow oil.



1 H), 2.75 (d, J = 13.5 Hz, 1 H), 4.17 (d, J = 11.4 Hz, 1 H), 4.26 (d,

J = 11.4 Hz, 1 H), 6.76 (d, J = 1.9 Hz, 2 H), 6.99 (t, J = 1.9 Hz, 1 H), 7.02

(t, J = 1.9 Hz, 1 H), 7.46 (d, J = 1.9 Hz, 2 H).


(Cq), 121.3 (2×CH), 127.2 (CH), 129.4 (2×CH), 130.6 (CH), 134.8 (2×Cq),

136.0 (2×Cq), 140.0 (Cq), 152.8 (Cq), 169.6 (Cq).

MS (EI) m/z (%): 434 (<1) [M+], 263 (10), 261 (64), 260 (14), 259 (99), 203 (11),

201 (65), 200 (12), 199 (100), 175 (38), 173 (58), 165 (13), 164 (24), 163

(12), 161 (17), 159 (24), 147 (44), 145 (77), 129 (22), 128 (11), 109 (14).



tR = 7.3 min.


36


(8p)

OHN

NCl

Cl

Cl Cl

C16H14Cl4N2OM = 392.11 g/mol




yellow oil.



J = 13.4 Hz, 1 H), 3.72 (d, J = 11.9 Hz, 1 H), 3.85 (d, J = 11.9 Hz, 1 H),

7.11 (d, J = 1.9 Hz, 2 H), 7.24 (t, J = 1.9 Hz, 1 H), 7.46 (t, J = 1.9 Hz, 1 H),

7.58 (d, J = 1.9 Hz, 2 H).


121.0 (2×CH), 126.9 (CH), 129.2 (2×CH), 130.5 (CH), 134.5 (2×Cq), 135.7

(2×Cq), 140.1 (Cq), 152.5 (Cq).

MS (EI) m/z (%): 392 (1) [M+], 364 (28), 362 (59), 360 (50), 219 (31), 218 (16), 217

(44), 216 (16), 203 (15), 201 (47), 200 (20), 199 (53), 198 (20), 189 (16),

187 (24), 175 (28), 173 (41), 165 (17), 164 (23), 163 (65), 162 (51), 161

(100), 160 (80), 159 (100), 147 (36), 145 (55), 135 (16), 133 (26), 125 (28),

124 (30), 123 (26), 115 (16), 89 (23).



tR = 10.4 min.


37

2.2.33 2-Amino-3-(3,4-dichlorophenyl)-2-methylpropan-1-ol (9)[5]

OHNH2

Cl

Cl

C10H13Cl2NOM = 234.12 g/mol

Racemic synthesis of amino alcohol rac-9 from acetate rac-7c

Acetate rac-7c (0.50 mmol, 217 mg) was dissolved in methanol (5 mL) and zinc dust

(15.0 mmol, 981 mg) and hydrochloric acid (6 M, 5 mL) were added. The resulting mixture

was heated to reflux for 4 hours, after which additional hydrochloric acid (6 M, 5 mL) was

added. The mixture was refluxed for another 15 hours, then allowed to cool to room

temperature and diluted with water (20 mL). The pH was adjusted with aqueous sodium

hydroxide (20%) to a value >12 and the reaction mixture was extracted with dichloromethane

(3 × 30 mL). The combined organic phases were dried over sodium sulfate and the solvent

was evaporated under reduced pressure. The pure product was obtained after column

chromatography (chloroform/methanol = 10:1, 1% diethyl amine) as a white solid

(0.39 mmol, 91.0 mg, 78%).

Synthesis of the enantiomerically enriched amino alcohol (S)-9 from acetate 7c

Acetate 7c (0.12 mmol, 51.1 mg, >99% ee) was dissolved in methanol (2 mL) and zinc dust

(3.5 mmol, 229 mg) and hydrochloric acid (6 M, 2 mL) were added. The resulting mixture

was heated to reflux for 20 hours, then allowed to cool to room temperature and diluted with

water (20 mL) The pH was adjusted with aqueous sodium hydroxide (20%) to a value >12

and the reaction mixture was extracted with dichloromethane (3 × 20 mL). The combined

organic phases were dried over sodium sulfate and the solvent was evaporated under reduced

pressure. The pure product was obtained after column chromatography

(chloroform/methanol = 10:1, 1% diethyl amine) as a white solid (61.5 µmol, 14.4 mg, 51%,

>99% ee).

Rf 0.35 (chloroform/methanol = 10:1, 1% diethyl amine)


1 H), 2.69 (d, J = 13.2 Hz, 1 H), 3.26-3.36 (m, 2 H), 7.06 (dd, J = 2.0 Hz,

J = 8.2 Hz, 1 H), 7.31 (d, J = 2.0 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H).


38

HPLC (Chiralpak® IC column; hexane/2-propanol = 95:5, 0.1% diethyl amine;

0.8 mL/min, 230 nm): tR = 15.5 min, 17.6 min.


2.2.34 3-(3,4-Dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol

(Cericlamine) (10)[5]

OHN

Cl

Cl

C12H17Cl2NOM= 262.18 g/mol

Racemic synthesis of compound rac-10 from amino alcohol rac-9

To amino alcohol rac-9 (0.38 mmol, 89.6 mg) were added aqueous formaldehyde (37%

solution, 3.70 mmol, 300 mg) and formic acid (13.0 mmol, 600 mg). The mixture was

refluxed for 4 hours. After cooling to room temperature, the reaction mixture was diluted with

water (15 mL), the pH was adjusted with aqueous sodium hydroxide (20%) to a value >12

and the reaction mixture was extracted with chloroform (3 × 15 mL). The combined organic

phases were dried over sodium sulfate and the solvent was evaporated under reduced


(chloroform/methanol = 10:1, 1% diethyl amine) as a yellowish solid (0.27 mmol, 70.4 mg,

71%).

Synthesis of the enantiomerically enriched compound (S)-10 from amino alcohol (S)-9

To amino alcohol (S)-9 (61.5 µmol, 14.4 mg, >99% ee) were added aqueous formaldehyde

(37% solution, 0.62 mmol, 50 mg) and formic acid (2.17 mmol, 100 mg). The mixture was

refluxed for 4.5 hours. After cooling to room temperature, the reaction mixture was diluted

with water (15 mL), the pH was adjusted with aqueous sodium hydroxide (20%) to a value

>12 and reaction mixture was extracted with chloroform (4 × 15 mL). The combined organic

phases were dried over sodium sulfate and the solvent was evaporated under reduced


(chloroform/methanol = 10:1, 1% diethyl amine) as a colourless, slowly crystallizing oil

(46.2 µmol, 12.1 mg, 75%, >99% ee).


39

Rf 0.30 (chloroform/methanol = 10:1, 1% diethyl amine)


1 H), 2.77 (d, J = 12.9 Hz, 1 H), 3.23 (d, J = 11.0 Hz, 1 H), 3.29 (d,

J = 11.0 Hz, 1 H), 7.06 (dd, J = 2.1 Hz, J = 8.2 Hz, 1 H), 7.30 (d,

J = 2.1 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 1 H).

HPLC (Chiralpak® IC column; hexane/2-propanol = 99.5:0.5; 0.4 mL/min,

250 nm): tR = 30.6 min, 31.7 min.

[α]20D +6.8 (c 0.8, EtOH) [Lit: [α]20

D +6.3 (c 1, EtOH)][5]


3. Optimization and screening experiments for the enzymatic kinetic

resolution

3.1 Solvent screening (Table 1)

Rac-7a (0.05 mmol, 17.8 mg) was dissolved in 2 mL of the solvent given in Table 1 (see

article). Lipase Candida antarctica B (CAL-B, formulation Novozym 435, 20.0 mg) was

added, the reaction vessel was stoppered and the mixture stirred at room temperature for 3

days. The reaction mixture was filtered and the solvent evaporated under reduced pressure.

The conversion and enantiomeric excess of the product 8a were determined by chiral HPLC-

chromatography.


40

3.2 Solvent screening with addition of benzylamine (Table 1)

Rac-7a (0.05 mmol, 17.8 mg) was dissolved in 2 mL of the solvent given in Table 1 (see

article). Benzylamine (3-10 eq) and lipase Candida antarctica B (CAL-B, formulation

Novozym 435, 20.0 mg) were added, the reaction vessel was stoppered and the mixture stirred

at room temperature for 3 days. The reaction mixture was filtered and the solvent evaporated

under reduced pressure. The conversion and enantiomeric excess of the product 8a were

determined by chiral HPLC-chromatography.

3.3 Reaction monitoring by HPLC for azo acetate 7b

Rac-7b (0.20 mmol, 66.5 mg) was dissolved in acetonitrile (8 mL). Benzylamine (1.00 mmol,

5 eq, 107 mg) and lipase Candida antarctica B (CAL-B, formulation Novozym 435, 80.0 mg)

were added, the reaction vessel was stoppered and the mixture stirred at room temperature for

7 days. Aliquots of the reaction mixture were drawn at intervals, filtered and the solvent

evaporated under reduced pressure. Conversion and enantiomeric excess of the product 8b

were determined by chiral HPLC.


41

Figure 1. Reaction monitoring by HPLC for 7b.

NN

F

OAc

F

*N

N

F

OH

F

CAL-B (80.0 mg)benzylamine (5 eq)

rac-7b (0.20 mmol) 8b

acetonitrile, RT

3.4 Substrate screening I (Table 2)

General procedure for compounds 7b-i: To a solution of azo acetate rac-7 (0.30 mmol) in

acetonitrile (12 mL) was added benzylamine (1.50 mmol, 5 eq, 161 mg) and lipase Candida

antarctica B (CAL-B, formulation Novozym 435, 120 mg). The reaction vessel was sealed,

and stirring was continued for 3 days. The reaction mixture was filtered and the solvent

evaporated under reduced pressure. The crude product was analyzed by HPLC to determine

conversion and enantiomeric excess of the product 8. For determination of the enantiomeric

excess of remaining azo acetate 7, the acetate was first separated by column chromatography

on silica gel (hexane/ethyl acetate = 4:1) and then converted to its corresponding alcohol 8

(see below).


42

Procedure for compound 7j: To a solution of azo acetate rac-7j (0.06 mmol, 23.2 mg) in

acetonitrile (2.4 mL) was added benzylamine (0.30 mmol, 5 eq, 32.2 mg) and lipase Candida

antarctica B (CAL-B, formulation Novozym 435, 24 mg). The reaction vessel was sealed,

and stirring was continued for 3 days. The reaction mixture was filtered and the solvent

evaporated under reduced pressure. The crude product was analyzed by HPLC to determine

conversion and the enantiomeric excess of the remaining substrate 7j and the product 8j.

Conversion of azo acetate 7b to azo alcohol 8b: To azo acetate 7b (0.07 mmol, 23.8 mg)

were added methanol (2 mL), water (2 mL) and methanolic potassium hydroxide (3 M, 2 mL).

The resulting mixture was stirred at room temperature for 2 hours, then diluted with water

(10 mL) and extracted with diethyl ether (3 × 10 mL). The combined organic phases were

washed with brine (1 × 15 mL) and dried over sodium sulfate. The solvent was evaporated

yielding a crude yellow oil containing the alcohol 8b, which was then analyzed by chiral

HPLC.

Conversion of azo acetates 7c-i to azo alcohols 8c-i: To the acetates 7c-i (0.03-0.07 mmol)

were added methanol (1 mL), water (0.5 mL) and potassium carbonate (0.14 mmol, 20.0 mg).

The resulting mixture was stirred at room temperature for 1 hour, then diluted with water

(10 mL) and extracted with diethyl ether (3 × 10 mL). The combined organic phases were

washed with brine (1 × 15 mL) and dried over sodium sulfate. The solvent was evaporated

yielding a crude yellow oil containing the alcohol 8c-i, which was then analyzed by chiral

HPLC.

3.5 Substrate screening II (Table 3)

General procedure for compounds 7c-d, k-p: To a solution of acetate rac-7 (0.20 mmol) in

acetonitrile (8 mL) was added benzylamine (1.00 mmol, 5 eq, 107 mg) and lipase Candida

antarctica B (CAL-B, formulation Novozym 435, 80.0 mg). The reaction vessel was sealed

and the mixture stirred for several hours. Aliquots of the reaction mixture were drawn at

various intervals, filtered and the solvent evaporated under reduced pressure. Conversion of

the product 8 was determined by HPLC.

Determination of the enantiomeric excess of compounds 7c-d, k-n, and 8c-d, k-n:

Enantiomeric excess of 8c-d, k-n was determined by chiral HPLC. For determination of the

enantiomeric excess of remaining azo acetates 7c-d, k-n, the aliquots drawn from the reaction

mixture were subjected to small scale column chromatography on silica gel (hexane/ethyl


43

acetate = 8:1) and the isolated acetate 7 saponified by addition of 0.3 mL of a mixture of

MeOH (9 mL), water (1 mL) and sodium carbonate (1.89 mmol, 200 mg). After standing for

2 hours, the reaction mixture was diluted with water (2 mL) and extracted with diethyl ether

(2 × 2 mL). The solvent was evaporated and the obtained alcohol 8 was analyzed by chiral

HPLC.

Determination of the enantiomeric excess of compound 7o: For determination of the

enantiomeric excess of azo acetate 7o, the aliquots drawn from the reaction mixture were

separated by small scale column chromatography on silica gel (hexane/ethyl acetate = 8:1).

Acetate 7o was saponified by addition of 0.3 mL of a mixture of MeOH (9 mL), water (1 mL)

and sodium carbonate (1.89 mmol, 200 mg). After standing for 2 hours, the reaction mixture

was diluted with water (2 mL), extracted with diethyl ether (2 × 2 mL) and the solvent

evaporated. The obtained crude alcohol 8o was then dissolved in dichloromethane (1 mL) and

converted to its phthalic acid monoester by addition of triethylamine (0.20 mmol, 20.0 mg)

and phthalic anhydride (0.14 mmol, 20.0 mg). The reaction mixture was stirred for 2 hours at

room temperature, then diluted with water (1 ml) and extracted with diethyl ether (2 × 1 mL).

The solvent was evaporated and the crude reaction mixture containing the phthalic acid

monoester was analyzed by chiral HPLC.

Phthalic acid mono-[3-(2,4-dichlorophenyl)-2-(2,4-dichlorophenylazo)-2-methylpropyl]ester

ON

NCl

Cl

Cl

Cl

COOHOC24H18Cl4N2O4

M = 540.22 g/mol


J = 13.9 Hz, 1 H), 4.67 (d, J = 11.3 Hz, 1 H), 4.71 (d, J = 11.3 Hz, 1 H),

7.08-7.12 (m, 2 H), 7.25 (dd, J = 2.2 Hz, J = 8.6 Hz, 1 H), 7.30-7.34 (m,

2 H), 7.48 (d, J = 2.1 Hz, 1 H), 7.55-7.60 (m, 2 H), 7.61-7.65 (m, 1 H), 7.83-

7.86 (m, 1 H).


44

HPLC (Chiralpak® IC column; hexane/2-propanol = 95:5, 0.1% trifluoroacetic

acid; 0.6 mL/min, 280 nm): tR = 20.2 min, 21.0 min.

Determination of the enantiomeric excess of 7p and 8p: For determination of the

enantiomeric excess of azo acetate 7p and azo alcohol 8p, the reaction mixture was filtered

after 12.5 hours, the solvent was evaporated, and the conversion was determined by HPLC.

Azo acetate 7p and azo alcohol 8p were separated by column chromatography on silica gel

(hexane/ethyl acetate = 4:1). 7p (0.06 mmol, 26.5 mg) and 8p (0.11 mmol, 43.3 mg) were

each dissolved in methanol (2 ml) and zinc dust (1.74/3.50 mmol, 114/229 mg) and

hydrochloric acid (6 M, 1/2 mL) were added. The two resulting mixtures were heated to reflux

for 17 hours, then allowed to cool to room temperature and diluted with water (10 mL). The

pH was adjusted with aqueous sodium hydroxide (20%) to a value >12 and the reaction

mixtures were extracted with dichloromethane (3 × 10 mL). The combined organic phases

were dried over sodium sulfate and the solvent was evaporated under reduced pressure. The

amino alcohols resulting from the reduction were purified by column chromatography

(chloroform/methanol = 10:1, 1% diethyl amine) to give colorless, slowly crystallizing oils

(0.04/0.05 mmol, 9.4/12.5 mg, 67/45%). The enantiomeric excess was determined by chiral

HPLC.

2-Amino-3-(3,5-dichlorophenyl)-2-methylpropan-1-ol

NH2OH

Cl

Cl

C10H13Cl2NOM = 234.12 g/mol

1H-NMR (360 MHz, CDCl3): δ = 1.05 (s, 3 H), 2.11 (br, 3 H), 2.60-2.76 (m, 2 H),

3.21–3.49 (m, 2 H), 7.11 (d, J = 1.9 Hz, 2 H), 7.25-7.27 (m, 1 H).

HPLC (Chiralpak® IC column; hexane/2-propanol = 95:5, 0.1% diethyl amine;

0.8 mL/min, 230 nm): tR = 13.7 min, 15.4 min.


45

3.6 Large-Scale enzymatic kinetic resolution of azo acetate 7c

Azo acetate rac-7c (5.00 mmol, 2.17 g) and benzylamine (25.0 mmol, 5 eq, 2.68 g) were

dissolved in acetonitrile (200 mL), and lipase Candida antarctica B (CAL-B, formulation

Novozym 435, 2.0 g) was added. The reaction course was followed by HPLC until a probe

taken from the reaction mixture (19.5 h) showed a conversion of 60%. The reaction mixture

was filtered and the solvent evaporated under reduced pressure. Column chromatography

(hexane/ethyl acetate = 8:1→ hexane/ethyl acetate = 2:1) gave the acetate (S)-7c (1.92 mmol,

835 mg, 38%, 97% ee) and the alcohol (R)-8c (2.86 mmol, 1.12 g, 57%, 59% ee) as yellow

oils. The enantiomeric excess of the alcohol 8c was determined by chiral HPLC. For

determination of the enantiomeric excess of azo acetate 7c, 5 mg (0.01 mmol) of the

compound were treated according to the procedure described in section 3.5 (page 42).


46

4. NMR-Spectra

4.1 Formation of N-benzylacetamide during enzymatic aminolysis

1H-NMR spectrum of enzymatic kinetic resolution of 7b as described in 3.4 (page 30) after 3 days

ppm (t1)0.01.02.03.04.05.06.07.0

0

5000

10000

15000

7.70

97.

684

7.66

9

7.32

37.

320

7.27

4

7.25

07.

154

7.15

0

7.13

17.

129

6.95

4

6.92

9

6.90

4

4.40

6

4.39

0

4.34

1

4.32

9

3.79

6

3.76

3

3.72

8

3.69

63.

139

3.12

5

3.11

7

3.10

1

3.04

4

3.00

6

2.03

8

1.98

2

1.23

9

1.19

9

2.75

0.420.47

1.71

3.13

1.101.03

1.163.00

2.10

1.01

1.13

Date:18 Dec 2011Document's Title:AGP262.mrc

Spectrum Title:AGP262inCDCl3,1H

Frequency (MHz):(f1) 360.132 Original Points Count:(f1) 32768 Actual Points Count:(f1) 65536 Acquisition Time (sec):(f1) 4.4039 Spectral Width (ppm):(f1) 20.661 Pulse Program:Unknown

NOAc

N

CAL-B(acetonitrile)F

F

NOH

NF

F

+ +NH2 NHAc


47

a) b)

c)

d)

1H-NMR spectrum of enzymatic kinetic resolution of 7b as described in 3.4 (page 30) after 3 days (magnification of 3.60-4.50 ppm)

ppm (t1)3.603.703.803.904.004.104.204.304.404.50

0

500

1000

1500

2000

2500

3000

3500

4.40

6

4.39

0

4.34

14.

329

3.83

9

3.79

6

3.76

3

3.72

8

3.69

6

0.42

0.47

1.10

1.03

2.10

Date:20 Dec 2011Document's Title:AGP262.mrc



Signals at 3.71 (d, J = 11.7 Hz, 1 H) and 3.78 (d, J = 11.7 Hz, 1 H) are related to alcohol 8b, signal at 4.40 (d, J = 5.7 Hz, 2 H) to N-

benzylacetamide, signals at 4.31 (d, J = 11.2 Hz, 1 H) and 4.36 (d, J = 11.2 Hz, 1 H) are related to remaining acetate 7b. Signal at 3.84 (s,

2 H) caused by excess benzylamine.

NN

F

OAc

F

b)

NN

F

OH

F

d)

HN

Oa)

NH2c)


48

4.2 Compounds 1H-Spectrum of 7c

ppm (t1)0.01.02.03.04.05.06.07.08.0

0

10000

20000

30000

40000

7.70

37.

697

7.21

37.

207

7.19

07.

184

6.98

76.

964

6.92

36.

901

6.46

36.

458

6.44

16.

435

4.31

54.

284

4.26

24.

230

2.82

0

2.78

22.

667

2.62

9

1.61

2

0.99

7

0.94

1.061.05

1.06

1.04

1.00

1.07

3.00

3.04

2.151.18

Date:17 Dec 2011Document's Title:7c.mrc

Spectrum Title:7c inC6D6,1H


OAcN

N

Cl

Cl

Cl

Cl


49

13C-Spectrum of 7c

ppm (t1)050100150

0

50000

10000

169.

620

150.

655

136.

921

135.

273

133.

865

132.

945

132.

446

131.

239

131.

099

130.

181

130.

148

123.

805

122.

413

72.8

80

67.6

58

41.1

42

20.2

0019

.431 Date:

17 Dec 2011Document's Title:7c 13C.mrc

Spectrum Title:7c inC6D6,13C


OAcN

N

Cl

Cl

Cl

Cl


50

1H-Spectrum of 8c

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

7.78

17.

778

7.77

47.

571

7.56

97.

567

7.34

47.

321

7.31

67.

310

7.05

57.

050

7.03

27.

027

3.84

43.

811

3.72

83.

695

3.13

63.

099

3.03

12.

994

1.21

8

1.07

2.13

0.891.92

1.16

1.03

1.00

3.03

Date:18 Dec 2011Document's Title:8c 1H.mrc

Spectrum Title:8c inCDCl3,1H


OHN

N

Cl

Cl

Cl

Cl


51

13C-Spectrum of 8c

ppm (t1)050100150

-1000

0

10000

20000

30000

40000

50000

60000

150.

253

137.

049

135.

110

133.

562

132.

556

132.

023

130.

914

130.

689

130.

116

129.

958

123.

440

122.

148

74.4

04

66.6

09

40.3

55

19.5

17 Date:17 Dec 2011Document's Title:8c 13C.mrc

Spectrum Title:8c inCDCl3,13C


OHN

N

Cl

Cl

Cl

Cl


52

1H-Spectrum of 7d

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

15000

20000

25000

300007.36

37.

348

7.22

47.

209

6.62

06.

606

4.39

34.

375

4.37

34.

354

2.91

22.

889

2.79

32.

770

1.60

5

1.10

0

2.001.98

2.01

2.05

1.03

2.99

3.05

Date:17 Dec 2011Document's Title:7d 1H.mrc

Spectrum Title:7d inC6D6,1H


OAcN

N

Br

Br


53

13C-Spectrum of 7d

ppm (t1)050100150

-1000

0

1000

2000

3000

4000

5000

6000

7000

169.

715

150.

635

135.

650

132.

634

132.

511

131.

428

125.

450

124.

118

121.

034

72.7

0467

.906

41.6

25

20.2

5619

.507 Date:

17 Dec 2011Document's Title:7d 13C.mrc

Spectrum Title:7d inC6D6,13C


OAcN

N

Br

Br


54

1H-Spectrum of 8d

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

15000

7.62

77.

602

7.56

97.

544

7.39

67.

373

7.09

67.

072

3.80

93.

776

3.72

43.

691

3.13

03.

093

3.00

72.

970

1.21

3

1.031.00

1.051.01

3.03

2.102.042.11

2.15

Date:17 Dec 2011Document's Title:8d 1H.mrc

Spectrum Title:8d inCDCl3,1H


OHN

N

Br

Br


55

13C-Spectrum of 8d

ppm (t1)050100150

0

10000

20000

30000

40000

150.

204

135.

834

132.

458

132.

322

131.

144

125.

320

123.

727

120.

502

74.0

44

66.7

56

40.7

75

19.5

71 Date:17 Dec 2011Document's Title:8d 13C.mrc

Spectrum Title:8d inCDCl3,13C


OHN

N

Br

Br


56

1H-Spectrum of 7j

ppm (t1)0.01.02.03.04.05.06.07.08.0

0

50000

10000

15000

8.36

48.

349

8.12

28.

108

7.78

27.

767

7.27

77.

264

7.26

3

4.44

44.

425

4.36

14.

342

3.39

63.

373

3.30

93.

286

2.08

4

1.30

8

2.002.01

2.04

2.43

1.031.04

1.041.05

3.08

3.07

Date:5 Mar 2012Document's Title:AGP404.mrc



OAcN

NO2N

NO2


57

13C-Spectrum of 7j

ppm (f1)050100150

0

5000

10000

15000

170.

432

154.

452

148.

941

146.

963

144.

057

131.

409

124.

789

123.

323

122.

923

73.6

01

67.3

72

41.7

10

20.8

1019

.884 Date:

5 Mar 2012Document's Title:AGP404 13C.mrc

Spectrum Title:AGP404inCDCl3,13C


OAcN

NO2N

NO2


58

1H-Spectrum of 8j

ppm (t1)0.01.02.03.04.05.06.07.08.0

0

50000

10000

15000

20000

8.37

28.

357

8.15

08.

135

7.81

77.

802

7.40

77.

392

3.93

03.

910

3.75

73.

737

3.33

73.

315

3.24

93.

226

1.26

9

2.00

2.02

2.13

2.08

1.031.04

1.061.06

3.15

Date:5 Mar 2012Document's Title:AGP405-1.mrc



OHN

NO2N

NO2


59

13C-Spectrum of 8j

ppm (f1)050100150

-5000

0

5000

10000

15000

20000

25000

30000

3500015

4.35

1

148.

963

146.

905

144.

635

131.

562

124.

815

123.

295

122.

929

75.4

26

66.5

06

40.8

96

19.5

79 Date:5 Mar 2012Document's Title:AGP405 13C.mrc



OHN

NO2N

NO2


60

1H-Spectrum of 7k

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

7.61

97.

595

7.44

77.

422

7.20

87.

185

7.02

06.

997

4.37

74.

346

4.33

14.

299

3.17

53.

137

3.12

03.

082

2.05

0

1.24

2

2.012.062.05

1.001.05

1.021.05

3.23

3.03

2.00

Date:7 Mar 2012Document's Title:7k 1H.mrc

Spectrum Title:AGP360-1inCDCl3,1H


OAcN

NCl

Cl


61

13C-Spectrum of 7k

ppm (t1)050100150

-1000

0

1000

2000

3000

4000

5000

170.

661

149.

994

136.

686

134.

934

132.

488

131.

910

129.

232

128.

188

123.

508

72.3

6767

.762

41.4

35

20.8

5719

.804 Date:

7 Mar 2012Document's Title:7k 13C.mrc

Spectrum Title:7k inCDCl3,13C


OAcN

NCl

Cl


62

1H-Spectrum of 8k

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

7.64

77.

623

7.46

47.

439

7.24

87.

225

7.15

77.

133

3.81

13.

778

3.72

73.

694

3.14

83.

111

3.02

12.

984

1.21

8

1.021.06

1.011.02

2.012.022.032.01

3.00

Date:7 Mar 2012Document's Title:8k 1H.mrc

Spectrum Title:AGP361-tinCDCl3,1H


OHN

NCl

Cl


63

13C-Spectrum of 8k

ppm (t1)050100150

-5000

0

5000

10000

15000

20000

25000

30000

35000149.

829

136.

932

135.

318

132.

406

132.

065

129.

329

128.

184

123.

493

74.0

24

66.7

74

40.7

27

19.5

97 Date:7 Mar 2012Document's Title:8k 13C.mrc



OHN

NCl

Cl


64

1H-Spectrum of 7l

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

100007.44

37.

418

7.35

17.

327

7.22

07.

196

6.49

96.

475

4.35

4

2.89

62.

858

2.77

32.

736

1.59

4

1.08

2

2.182.002.04

2.05

2.06

1.001.01

3.07

3.03

Date:7 Mar 2012Document's Title:7l 1H.mrc

Spectrum Title:7l inC6D6,1H


OAcN

N

I

I


65

13C-Spectrum of 7l

ppm (t1)050100150

0

50000

169.

686

151.

263

138.

565

137.

427

136.

305

132.

901

124.

172

97.6

3892

.424

72.7

1367

.903

41.7

51

20.2

5619

.516 Date:

7 Mar 2012Document's Title:7l 13C.mrc

Spectrum Title:7l inC6D6,13C


OAcN

N

I

I


66

1H-Spectrum of 8l

ppm (t1)0.01.02.03.04.05.06.07.08.0

0

50000

10000

7.83

87.

814

7.59

57.

572

7.42

67.

402

6.97

06.

947

3.80

23.

770

3.71

63.

683

3.11

13.

074

2.98

52.

948

1.20

7

2.022.022.01

2.07

1.061.01

1.051.02

3.00

Date:7 Mar 2012Document's Title:8l 1H.mrc

Spectrum Title:AGP330-CinCDCl3,1H


OHN

N

I

I


67

13C-Spectrum of 8l

ppm (t1)050100150

-1000

0

10000

20000

30000

40000

50000

150.

775

138.

327

137.

113

136.

479

132.

777

123.

831

97.4

90

91.9

32

74.0

45

66.7

26

40.8

57

19.5

63 Date:7 Mar 2012Document's Title:8l 13C.mrc

Spectrum Title:AGP330-CinCDCl3,13C


OHN

N

I

I


68

1H-Spectrum of 7m

ppm (t1)0.01.02.03.04.05.06.07.0

0

5000

7.67

77.

675

7.55

67.

553

7.53

2

7.35

47.

350

7.33

67.

328

7.18

37.

179

7.16

1

7.08

37.

076

7.06

17.

044

7.03

64.

513

4.48

14.

450

3.53

03.

492

3.43

43.

396

2.03

8

1.35

1

1.00

3.02

3.00

1.041.02

2.10

1.042.113.051.02

Date:7 Mar 2012Document's Title:7m 1H.mrc

Spectrum Title:7m inCDCl3,1H


OAcN

NBr

Br


69

13C-Spectrum of 7m

ppm (t1)050100150

0

5000

10000

15000170.

770

149.

132

136.

427

133.

451

133.

126

132.

511

131.

440

128.

252

127.

973

127.

042

126.

107

124.

106

117.

899

74.3

29

68.0

38

40.7

91

20.9

06

19.5

62 Date:7 Mar 2012Document's Title:7m 13C.mrc

Spectrum Title:7m inCDCl3,13C


OAcN

NBr

Br


70

1H-Spectrum of 8m

ppm (t1)0.01.02.03.04.05.06.07.0

0

10000

20000

30000

40000

50000

60000

70000

7.57

47.

572

7.56

17.

559

7.40

57.

402

7.36

7

7.30

47.

301

7.24

07.

238

7.22

87.

226

7.21

57.

213

7.09

87.

096

7.08

57.

083

7.07

37.

070

3.86

33.

843

3.83

93.

819

3.48

43.

461

3.32

93.

306

2.91

8

1.38

6

1.001.02

1.081.05

4.24

2.15

1.071.06

3.16

0.80

Date:7 Mar 2012Document's Title:8m 1H.mrc

Spectrum Title:8m inCDCl3,1H


OHN

NBr

Br


71

13C-Spectrum of 8m

ppm (t1)050100150

0

5000

10000

15000

148.

393

136.

725

133.

402

133.

018

132.

797

131.

900

128.

192

128.

109

127.

084

126.

130

124.

524

117.

762

75.7

90

66.8

54

40.3

58

19.8

08 Date:7 Mar 2012Document's Title:8m 13C.mrc

Spectrum Title:AGP332-1CinCDCl3,13C


OHN

NBr

Br


72

1H-Spectrum of 7n

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

15000

7.78

77.

783

7.78

07.

627

7.62

37.

615

7.61

37.

612

7.61

07.

584

7.58

27.

571

7.56

97.

567

7.36

97.

356

7.34

3

7.27

07.

267

7.26

47.

123

7.11

07.

097

7.02

27.

009

4.39

04.

371

4.32

64.

307

3.16

93.

146

3.11

93.

096

2.06

6

1.25

6

1.101.06

2.19

1.09

1.12

1.011.061.00

1.11

3.11

3.01

1.061.09

Date:7 Mar 2012Document's Title:7n 1H.mrc

Spectrum Title:7n inCDCl3,1H


OAcN

N

Br

Br


73

13C-Spectrum of 7n

ppm (t1)050100150

0

5000

10000

170.

651

152.

596

138.

747

133.

727

133.

443

130.

393

129.

718

129.

602

129.

200

124.

386

123.

008

122.

106

122.

000

72.5

9867

.696

41.6

86

20.8

6119

.865 Date:

7 Mar 2012Document's Title:7n 13C.mrc

Spectrum Title:7n inCDCl3,13C


OAcN

N

Br

Br


74

1H-Spectrum of 8n

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

15000

20000

7.66

17.

660

7.65

87.

648

7.64

67.

598

7.59

77.

585

7.58

37.

582

7.38

47.

371

7.35

87.

151

7.15

07.

128

3.82

33.

803

3.74

93.

730

3.13

93.

117

3.02

53.

003

2.33

4

1.23

1

1.001.051.003.202.08

1.101.04

1.111.09

3.20

0.93

Date:7 Mar 2012Document's Title:8n 1H.mrc

Spectrum Title:8n inCDCl3,1H


OHN

N

Br

Br


75

13C-Spectrum of 8n

ppm (t1)050100150

-5000

0

5000

10000

15000

20000152.

397

139.

162

133.

722

133.

627

130.

462

129.

633

129.

588

129.

408

124.

188

123.

108

122.

192

122.

125

74.3

05

66.7

25

40.9

44

19.5

88 Date:7 Mar 2012Document's Title:8n 13C.mrc

Spectrum Title:AGP329CinCDCl3,13C


OHN

N

Br

Br


76

1H-Spectrum of 7o

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

15000

20000

7.52

57.

521

7.36

87.

364

7.31

37.

299

7.28

67.

283

7.27

27.

269

7.13

17.

128

7.11

87.

114

4.46

14.

443

4.42

54.

406

3.41

83.

395

3.32

33.

300

2.03

5

1.31

4

0.971.001.041.041.041.07

1.081.08

1.061.07

3.09

3.11

Date:7 Mar 2012Document's Title:7o 1H.mrc

Spectrum Title:7o inCDCl3,1H


OAcN

NCl

Cl

Cl

Cl


77

13C-Spectrum of 7o

ppm (t1)050100150

-5000

0

5000

10000

15000

20000

170.

630

146.

379

136.

959

135.

780

135.

144

133.

325

133.

160

133.

093

130.

252

129.

489

127.

714

126.

727

118.

461

74.3

29

67.8

26

37.8

44

20.8

1919

.560 Date:

7 Mar 2012Document's Title:7o 13C.mrc

Spectrum Title:7o inCDCl3,13C


OAcN

NCl

Cl

Cl

Cl


78

1H-Spectrum of 8o

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

15000

20000

7.36

77.

352

7.30

77.

303

7.29

37.

289

7.27

57.

261

7.17

67.

172

7.16

27.

159

3.85

13.

830

3.78

33.

762

3.40

43.

381

3.21

13.

188

1.33

4

1.06

0.950.971.061.061.25

1.101.11

1.091.09

3.05

Date:7 Mar 2012Document's Title:8o 1H.mrc

Spectrum Title:AGP333CinCDCl3,1H


OHN

NCl

Cl

Cl

Cl


79

13C-Spectrum of 8o

ppm (t1)050100

0

5000

10000

15000137.

401

135.

786

135.

243

133.

616

133.

425

133.

056

130.

246

129.

378

127.

868

126.

801

118.

245

75.8

86

66.8

12

37.3

31

19.6

85 Date:7 Mar 2012Document's Title:8o 13C.mrc

Spectrum Title:AGP333CinCDCl3,13C


OHN

NCl

Cl

Cl

Cl


80

1H-Spectrum of 7p

ppm (t1)0.01.02.03.04.05.06.07.0

0

50000

10000

7.46

07.

454

7.02

87.

022

7.01

76.

995

6.99

06.

984

6.76

76.

762

4.27

14.

239

4.18

74.

155

2.76

92.

731

2.60

12.

563

1.58

9

0.93

0

1.071.04

2.061.001.04

2.01

1.121.08

3.06

3.01

Date:7 Mar 2012Document's Title:7p 1H.mrc

Spectrum Title:7p inC6D6,1H


OAcN

NCl

Cl

Cl Cl


81

13C-Spectrum of 7p

ppm (t1)050100150

0

50000

10000

169.

550

152.

847

139.

991

135.

961

134.

820

130.

633

129.

436

127.

210

121.

265

73.0

19

67.4

92

41.3

35

20.1

4719

.353 Date:

7 Mar 2012Document's Title:7p 13C.mrc

Spectrum Title:7p inC6D6,13C


OAcN

NCl

Cl

Cl Cl


82

1H-Spectrum of 8p

ppm (t1)0.01.02.03.04.05.06.07.0

0

10000

20000

30000

7.57

77.

574

7.46

37.

459

7.45

67.

247

7.24

47.

240

7.11

27.

109

3.85

53.

835

3.73

23.

712

3.12

33.

101

3.02

23.

000

1.22

0

1.021.002.05

2.14

1.141.11

1.121.13

3.24

Date:7 Mar 2012Document's Title:8p 1H.mrc

Spectrum Title:AGP334CinCDCl3,1H


OHN

NCl

Cl

Cl Cl


83

13C-Spectrum of 8p

ppm (t1)050100150

-1000

0

10000

20000

30000

40000

50000

60000152.

540

140.

092

135.

743

134.

546

130.

517

129.

183

126.

883

121.

002

74.6

91

66.5

01

40.5

68

19.5

29 Date:7 Mar 2012Document's Title:8p 13C.mrc

Spectrum Title:8p inCDCl3,13C


OHN

NCl

Cl

Cl Cl


84

5. References

[1] M. R. Heinrich, O. Blank, D. Ullrich, M. Kirschstein, J. Org. Chem. 2007, 72, 9609–

9616.

[2] O. Blank, A. Wetzel, D. Ullrich, M. R. Heinrich, Eur. J. Org. Chem. 2008, 3179–

3189.

[3] M. R. Heinrich, O. Blank, A. Wetzel, J. Org. Chem. 2007, 72, 476–484.

[4] Dietz, F. R.; Prechter, A.; Gröger, H.; Heinrich, M. R. Tetrahedron Lett. 2011, 52,

655−657.

[5] B. Kaptein, H. M. Moody, Q. B. Broxterman, J. Kamphuis, J. Chem. Soc. Perkin

Trans. I 1994, 1495–1498.


synthesis of (s)-(+)-cericlamine through lipase … of (s)-(+)-cericlamine through lipase-catalyzed...

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