mechanistic aspects of vinca-type dimers superacidic ... · 1 equiv) and (r)-koga’s amine (686...
TRANSCRIPT
S1
Supporting Information
Enantioselective Synthesis of Levomilnacipran
Julien Alliot, Edmond Gravel, Florence Pillon, David-Alexandre Buisson, Marc Nicolas, and
Eric Doris.
General ................................................................................................................................... 2
N1-N3-bis((R)-1-phenyl-2-(piperidin-1-yl)ethyl)propane-1,3-diamine (Koga’s amine) ........ 3
(2S)-phenylpent-4-enoic acid (3) ........................................................................................... 5
(3S,5R)-5-(iodomethyl)-3-phenyldihydrofuran-2(3H)-one (4) .............................................. 7
Methyl 3-((S)-oxiran-2-yl)-2-phenylpropanoate (5) .............................................................. 9
(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one (2) ........................................................ 11
(1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide (7) .............. 13
(1S,2R)- 2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (8) ................. 15
(1S,2R)-2-((1,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1-
phenylcyclopropanecarboxamide (9) ................................................................................... 17
(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (1) .................. 19
(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide ....................... 21
hydrochloride (1·HCl) ......................................................................................................... 21
Model for the selective deprotonation of epoxy-ester 5 ....................................................... 23
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General
Unless otherwise specified, chemicals were purchased from Aldrich and used without further
purification. Reactions were carried out under nitrogen using dry solvents, unless otherwise
stated. THF was distilled from sodium/benzophenone before use. 1,4-Dioxane and toluene
were distilled from sodium and stored under argon over 4Å molecular sieve. Flash
chromatography was carried out on Kieselgel 60 (230–240 mesh, Merck) and analytical TLC
was performed on Merck precoated silica gel plates (60 F254); visualization was carried out
with UV and/or heating with a solution of KMnO4 in water. HRMS were recorded at the
“Service de Spectrométrie de Masse de l’Institut de Chimie des Substances Naturelles” in
Gif-sur-Yvette (France). 1H and 13C NMR spectra were recorded on a Bruker Avance DPX
400 spectrometer at 400 and 100 MHz respectively. Chemical shifts (δ) are given in ppm and
coupling constants (J) in hertz. IR spectra were recorded on a Perkin-Elmer System 2000 FT-
IR. Optical rotations were determined using the sodium D line (589 nm) on a Perkin Elmer
341 polarimeter.
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N1-N3-bis((R)-1-phenyl-2-(piper idin-1-yl)ethyl)propane-1,3-diamine (Koga’s amine)1
Under N2, (R)-styrene oxide (2 g, 16.6 mmol, 1 equiv) was
diluted in EtOH (10 mL) before piperidine (2 mL, 1.2
equiv) was added. The solution was heated to reflux for 5 h. Volatiles were removed under
vacuum by azeotropic distillation with toluene (2 × 6 mL). The mixture was then diluted in
MTBE (18 mL) before NEt3 (8.7 mL, 3.8 equiv) was added. After 10 min at rt, the reaction
mixture was cooled down to –15 °C and stirred for additional 10 min. Methane sulfonyl
chloride (1.54 mL, 1.2 equiv) was then added dropwise over 25 min and under vigorous
stirring. After 40 min at –15 °C, 1,3-diaminopropane (0.7 mL, 0.5 equiv) was added, followed
by H2O (8.2 mL). The reaction mixture was warmed to rt over 1 h during which time the
precipitate dissolved. The organic phase was collected and the aqueous layer was extracted
with MTBE (2 × 10 mL). The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude residue (3.1 g) was first
purified by flash chromatography (CH2Cl2/MeOH/NH4OH 99:0.5:0.5 → 85:14.5:0.5). The
product was then recrystallized from i-PrOH/H2O at 0 °C, collected and dried under vacuum
for 72 h. The title compound was recovered as a white solid (2.3 g, 62%).
1H NMR (CDCl3): δ 1.33–1.68 (14H, m), 2.21–2.53 (18H, m), 3.71 (2H, dd, J = 10.8 Hz, J =
3.5 Hz), 7.21–7.36 (10H, m).
13C NMR (CDCl3): δ 24.5, 26.1, 31.5, 46.2, 54.6, 60.1, 66.6, 126.8, 127.3, 128.2, 143.3.
IR (neat): 3301, 2934, 2801, 1452 cm-1.
[α]20 D –111.6 (c 0.56, CHCl3); (lit.,1 [α]20
D –112 (c 5.45, CHCl3), 99.9% ee).
MS (ES+): 449 [M+H]+.
1 Org. Process Res. Dev. 2007, 11, 215.
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1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm
1.484
1.499
1.509
1.524
1.539
1.547
1.563
1.578
1.646
1.662
1.679
2.213
2.222
2.244
2.253
2.390
2.418
2.446
2.461
2.495
2.512
3.700
3.708
3.727
3.736
7.218
7.236
7.263
7.279
7.298
7.316
7.333
7.351
14.6
2
18.0
2
2.00
10.8
9
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
24.448
26.077
30.477
46.227
54.572
60.129
66.558
76.620
76.937
77.254
126.846
127.304
128.177
143.273
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S5
(2S)-phenylpent-4-enoic acid (3)2
Under N2 and at 0 °C, to a solution of phenylacetic acid (200 mg, 1.47 mmol,
1 equiv) and (R)-Koga’s amine (686 mg, 1.04 equiv) in dry THF (10 mL), n-
BuLi (2.35 mL of a 2.5 M soln in hexane, 4 equiv) was added over 5 min. The
reaction mixture was stirred at 0 °C for 15 min, cooled down to –78 °C, and allyl bromide
(509 µL, 4 equiv) was added over 10 min. After the addition, the reaction was immediately
quenched with MeOH/THF 1:3 (1.9 mL) and stirred for 5 min. 1 M HCl (10 mL) and EtOAc
(10 mL) were added. The organic phase was collected and the aqueous layer was extracted
with EtOAc (2 × 10 mL). The combined organic layers were washed with 1 M HCl (5 mL),
brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give
compound 3 (214 mg, 83%) as a yellowish oil. No further purification was needed for this
product.
Rf 0.40 (MeOH/CH2Cl2 4:96).
1H NMR (CDCl3): δ 2.49–2.57 (1H, m), 2.79–2.87 (1H, m), 3.65 (1H, dd, J = 8.0 Hz, J = 7.6
Hz), 5.02 (1H, dd, , J = 10.0 Hz, J = 1.6 Hz), 5.09 (1H, dd, J = 17.2 Hz, J = 1.6 Hz), 5.67–
5.78 (1H, m), 7.25–7.37 (5H, m).
13C NMR (CDCl3): δ 36.9, 51.2, 117.1, 127.5, 127.9 (2C), 128.6, (2C), 134.8, 137.7, 179.0.
IR (neat): 3067, 1706, 1415, 918, 697 cm-1.
Chiral HPLC: Chiralcel OJ 250 × 4.6 mm, n-hexane/i-PrOH 9:1, flow rate: 1 mL min-1,
detection at 220 nm, tmajor = 9.6 min, tminor = 11.5 min, 88% ee.
[α]20 D +77.6 (c 0.85, CHCl3); (lit.,2 [α]20
D +77.2 (c 1.00, CHCl3), 93% ee).
MS (ES+): 177 [M+H]+.
2 J. Am. Chem. Soc. 2011, 133, 11936.
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9.5 9.0 8.5 8.0 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 ppm
2.499
2.516
2.534
2.552
2.569
2.794
2.812
2.831
2.848
2.868
3.633
3.652
3.672
5.007
5.032
5.067
5.071
5.110
5.113
5.676
5.693
5.701
5.710
5.718
5.736
5.744
5.753
5.761
5.778
7.263
7.277
7.287
7.291
7.298
7.311
7.324
7.332
7.356
1.01
1.00
0.99
0.98
0.98
0.96
4.82
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
36.997
51.192
76.627
76.944
77.261
117.222
127.532
127.983
128.643
134.797
137.736
179.036
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(3S,5R)-5-(iodomethyl)-3-phenyldihydrofuran-2(3H)-one (4)
Under N2 and at 0 °C, to a solution of acid 3 (330 mg, 1.87 mmol, 1 equiv) in
Et2O (12 mL), K2CO3 (310 mg, 1.2 equiv) was added, followed by I2 (522 mg,
1.1 equiv) portionwise over 20 min. The dark mixture was stirred at 0 °C for 1
h and 5 h at rt. Iodide in excess was neutralized with sat Na2S2O3 (5 mL). The organic phase
was collected and the aqueous layer was extracted with Et2O (2 × 5 mL). The combined
organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude mixture was purified by flash chromatography (EtOAc/n-
hexane 2:8) to give cis-isomer 4 as a white solid (365 mg, 65%).
Spectral data obtained for 4 are in agreement with those previously reported in the literature
for the racemic iodolactone.3
Rf 0.40 (EtOAc/c-hexane 3:7).
1H NMR (CDCl3): δ 2.10–2.19 (1H, m), 2.92–2.99 (1H, m), 3.37 (1H, dd, J = 10.6 Hz, J =
7.2 Hz), 3.53 (1H, dd, J = 10.6 Hz, J = 4.4 Hz), 3.95 (1H, dd, J = 12.4 Hz, J = 8.8 Hz), 4.48–
4.55 (1H, m), 7.25–7.40 (5H, m).
13C NMR (CDCl3): δ 6.4, 38.3, 47.3, 76.1, 127.8, 128.0 (2C), 128.8 (2C), 135.9, 175.7.
IR (KBr): 1771, 1154, 1005, 698 cm-1.
Chiral HPLC: Daicel OJ-R 150 × 4.6 mm, H2O/MeOH 1:9, flow rate: 1 mL min-1, detection
at 254 nm, tminor = 4.1 min, tmajor = 5.0 min, 88% ee.
[α]20 D +30.9 (c 0.50, CHCl3).
MS (ES+): 303 [M+H]+.
3 J. Med. Chem. 1992, 35, 885.
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9.5 9.0 8.5 8.0 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 ppm
1.547
2.108
2.133
2.140
2.165
2.172
2.197
2.928
2.942
2.950
2.960
2.964
2.974
2.982
2.996
3.353
3.371
3.379
3.397
3.505
3.515
3.531
3.542
3.930
3.952
3.961
3.983
4.485
4.499
4.504
4.510
4.515
4.518
4.521
4.524
4.529
4.535
4.540
4.554
7.263
7.301
7.317
7.322
7.337
7.339
7.369
7.386
7.404
1.07
1.07
1.05
1.07
1.01
1.00
4.76
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
6.431
38.382
47.365
76.171
76.625
76.942
77.147
77.260
127.799
128.040
128.895
135.925
175.793
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S9
Methyl 3-((S)-oxiran-2-yl)-2-phenylpropanoate (5)
To a solution of lactone 4 (264 mg, 0.87 mmol, 1 equiv) in MeOH (8.7 mL)
K2CO3 (241 mg, 2 equiv) was added. The mixture was stirred for 2 h at rt, and
the solvent was removed in vacuo. The solid was suspended in Et2O, filtered,
and washed twice with Et2O (2 × 4 mL). Volatiles were evaporated under vacuum to give
compound 5 as a colorless oil (175 mg, 98%).
Rf 0.35 (EtOAc/c-hexane 3:7).
1H NMR (CDCl3): δ 1.80–1.87 (1H, m), 2.11–2.17 (2H, m), 2.40–2.47 (2H, m), 2.51–2.53
(1H, m), 2.67–2.70 (1H, m), 2.75–2.80 (2H, m), 2.95–2.98 (1H, m), 3.67 (3H, s), 3.68 (3H, s),
3.78–3.84 (2H, m), 7.27–7.37 (10H, m).
13C NMR (CDCl3): δ 36.1, 36.4, 47.2, 47.3, 48.3, 48.4, 49.9, 50.3, 52.0, 52.1, 127.4, 127.5
(2C), 127.6, 127.7 (2C), 127.9 (2C), 128.7 (2C), 137.9, 138.5, 173.6, 173.7.
IR (neat): 1734, 1260, 1167 cm-1.
MS (ES+): 207 [M+H]+.
HRMS: calcd for C12H15O3 [M+H]+ 207.1017, found 207.1023.
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9.5 9.0 8.5 8.0 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 ppm
1.860
2.140
2.155
2.159
2.174
2.410
2.420
2.426
2.433
2.445
2.507
2.514
2.519
2.526
2.674
2.684
2.696
2.752
2.763
2.775
2.784
2.792
2.955
2.961
2.966
2.972
2.978
3.674
3.684
3.783
3.802
3.812
3.823
3.837
7.262
7.271
7.290
7.299
7.307
7.316
7.333
7.346
1.02
2.04
2.00
1.03
1.00
2.02
1.00
5.95
2.06
9.27
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
36.163
36.453
47.242
47.322
48.365
48.466
49.963
50.376
52.098
52.130
76.669
76.987
77.305
127.441
127.492
127.591
127.744
127.949
128.747
128.848
137.991
138.503
173.626
173.745
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S11
(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one (2)
LDA (2 mL of a 0.6 M soln in THF, 1.2 equiv) was added to a refluxing solution
of epoxy ester 5 (202 mg, 0.98 mmol, 1 equiv) in anhydrous 1,4-dioxane (9 mL)
and HMPA (1.2 mL). After 2 min, the reaction was cooled down to rt and HCl
was bubbled until pH < 1. Et2O (10 mL) and H2O (10 mL) were added. The organic phase
was collected and the aqueous layer was extracted with Et2O (2 × 10 mL). The combined
organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The cyclopropyl lactone was separated from the trans-cyclopropane
by column chromatography (EtOAc/c-hexane 2:8) to afford compound 2 as a colorless liquid
(94 mg, 55%).
Spectral data obtained for 2 are in agreement with those previously reported in the literature.4
Rf 0.40 (EtOAc/c-hexane 3:7).
1H NMR (CDCl3): δ 1.37 (1H, t, J = 4.8 Hz), 1.65 (1H, dd, J = 7.6 Hz, J = 4.8 Hz), 2.54–2.58
(1H, m), 4.29 (1H, d, J = 9.4 Hz), 4.47 (1H, dd, J = 9.4 Hz, J = 4.8 Hz), 7.28–7.45 ppm (5H,
m).
13C NMR (CDCl3): δ 20.0, 25.0, 31.6, 67.9, 127.6, 128.2 (2C), 128.5 (2C), 134.0, 175.9 ppm.
IR (neat): 1760, 1249 cm-1.
Chiral HPLC: Daicel OJ-R 150 × 4.6 mm, H2O/MeOH 4:6, flow rate: 1 mL min-1, detection
at 254 nm, tmajor = 15.4 min, tminor = 17.7 min, 88% ee.
[α]20D –62.4 (c 0.48, MeOH); (lit.,5
MS (ES+): 175 [M+H]+.
[α]20D –78.5 (c 1.42, MeOH), 96% ee).
4 Bioorg. Med. Chem. Lett. 2007, 17, 2834. 5 J. Org. Chem. 1996, 61, 915.
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1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm
1.366
1.378
1.390
1.546
1.642
1.654
1.661
1.673
2.554
2.565
2.573
4.292
4.315
4.460
4.471
4.482
4.494
7.263
7.300
7.318
7.341
7.360
7.378
7.423
7.441
7.445
1.03
1.00
0.94
0.99
1.00
4.84
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
20.072
25.018
31.635
67.994
76.622
76.940
77.143
77.257
127.630
128.233
128.552
134.005
175.923
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S13
(1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide (7)
Under N2, diethylamine (210 µL, 2.6 equiv) was added to a suspension
of AlCl3 (137 mg, 1.3 equiv) in anhydrous toluene (1.5 mL). After 10
min, lactone 2 (138 mg, 0.79 mmol, 1 equiv) diluted in toluene (2 mL)
was added dropwise. The suspension was stirred for 2 h and quenched with 0.1 N HCl (3 mL).
The organic phase was collected and the aqueous layer extracted with toluene (2 × 3 mL). The
combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude mixture was purified by filtration over silica
(CH2Cl2/EtOAc 99:1 → 80:20) to give compound 7 as a colorless oil (176 mg, 90%).
Spectral data obtained for 7 are in agreement with those previously reported in the literature.6
Rf 0.10 (EtOAc/c-hexane 3:7).
1H NMR (CDCl3): δ 0.91 (3H, t, J = 7.0 Hz), 1.09 (1H, t, J = 5.6 Hz), 1.13 (3H, t, J = 8.4
Hz), 1.54–1.60 (1H, m), 1.66 (1H, dd, J = 8.4 Hz, J = 5.6 Hz), 2.35 (1H, brs), 3.18 (1H, dd, J
= 12.0 Hz, J = 10.4 Hz), 3.35–3.43 (3H, m), 3.47-3.55 (1H, m), 4.05 (1H, dd, J = 12.4 Hz, J =
4.8 Hz), 7.19–7.32 (5H, m).
13C NMR (CDCl3): δ 12.3, 13.0, 16.6, 31.9, 34.3, 39.4, 41.9, 64.8, 125.6, 126.5, 128.6, 140.2,
171.1.
IR (neat): 3418, 1616, 1431, 699 cm-1.
[α]20 D +50.8 (c 0.51, CHCl3).
MS (ES+): 248 [M+H]+.
6 Adv. Synth. Catal. 2001, 343, 299.
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S14
1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm
1.126
1.144
1.162
1.549
1.560
1.571
1.583
1.641
1.655
1.663
1.676
2.357
3.151
3.177
3.181
3.207
3.353
3.371
3.389
3.394
3.406
3.412
3.423
3.429
3.487
3.505
3.523
3.541
4.030
4.041
4.060
4.072
7.194
7.212
7.221
7.232
7.240
7.263
7.281
7.300
7.319
2.91
1.11
2.91
0.98
0.99
1.10
2.87
1.10
0.97
3.14
2.13
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
12.305
13.079
16.645
31.939
34.315
39.475
41.921
64.847
76.617
76.934
77.139
77.252
125.671
126.568
128.631
140.218
171.184
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S15
(1S,2R)- 2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (8)
Under N2, SOCl2 (77 µL, 1.6 equiv) was added dropwise to a solution of
alcohol 7 (164 mg, 0.66 mmol, 1 equiv) in anhydrous toluene (4 mL).
After 2 h, volatiles were removed in vacuo. The crude residue was
purified by filtration over silica gel (CH2Cl2/EtOAc 99:1 → 80:20) to give compound 8 as a
white solid (168 mg, 96%).
Rf 0.60 (EtOAc/c-hexane 3:7).
1H NMR (CDCl3): δ 0.55 (3H, t, J = 7.1 Hz), 1.12 (3H, t, J = 7.4 Hz), 1.18 (1H, dd, J = 9.2
Hz, J = 5.2 Hz), 1.61–1.66 (1H, m), 2.16–2.21 (1H, m), 3.04–3.10 (1H, m), 3.12–3.19 (1H,
m), 3.50–3.70 (4H, m), 7.20–7.33 (5H, m).
13C NMR (CDCl3): δ 12.2, 12.3, 21.2, 26.9, 37.3, 39.6, 42.3, 45.6, 126.5 (2C), 126.8, 128.7
(2C), 140.2, 168.9.
IR (KBr): 1630, 1427, 1141, 699 cm-1.
[α]20 D +146 (c 0.62, CHCl3).
MS (ES+): 266 [M+H]+.
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1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm
1.136
1.161
1.173
1.183
1.196
1.550
1.627
1.641
1.655
2.167
2.184
2.205
3.040
3.058
3.076
3.094
3.136
3.153
3.169
3.187
3.515
3.532
3.549
3.568
3.586
3.598
3.616
3.643
3.662
3.672
3.691
7.205
7.222
7.232
7.251
7.263
7.291
7.310
7.329
2.53
2.54
0.96
0.95
0.97
1.01
1.00
3.73
2.90
1.77
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
12.184
12.246
21.243
26.924
37.302
39.648
42.355
45.580
76.684
77.001
77.319
126.466
126.752
128.743
140.252
168.888
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S17
(1S,2R)-2-((1,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1-
phenylcyclopropanecarboxamide (9)
Under N2, cyclopropane 8 (120 mg, 0.45 mmol, 1 equiv) was
diluted in anhydrous toluene (2 mL) and potassium phtalimide
(167 mg, 2 equiv) was added. The reaction mixture was heated to
reflux for 3 h, cooled down to rt, and quenched with H2O (3 mL). The organic phase was
collected and the aqueous layer was extracted with toluene (2 × 3 mL). The combined organic
layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure to give 9 as a white solid (148 mg, 88%).
Spectral data obtained for 9 are in agreement with those previously reported in the literature.7
Rf 0.30 (EtOAc/cyclohexane 3:7).
1H NMR (CDCl3): δ 0.65 (3H, t, J = 7.0 Hz), 1.08–2.19 (4H, m), 1.65 (1H, t, J = 5.8 Hz),
1.99–2.05 (1H, m), 3.10–3.17 (1H, m), 3.29–3.35 (1H, m), 3.41–3.49 (2H, m), 3.53–3.59 (1H,
m), 4.16 (1H, dd, J = 14.0 Hz, J = 4.0 Hz), 7.10–7.35 (5H, m), 7.68–7.73 (2H, m), 7.81–7.85
(2H, m).
13C NMR (CDCl3): δ 12.5, 12.7, 20.6, 24.5, 34.8, 39.3, 39.5, 41.8, 128.1 (2C), 126.0 (2C),
126.5, 128.6 (2C), 132.1 (2C), 133.9 (2C), 140.3, 168.2 (2C), 169.1.
IR (KBr): 1771, 1714, 1632, 1426, 1386, 722 cm-1.
[α]20 D –64.6 (c 0.46, CHCl3).
MS (ES+): 377 [M+H]+.
7 J. Med. Chem. 1987, 30, 318.
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S18
9.5 9.0 8.5 8.0 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 ppm
1.166
1.180
1.193
1.643
1.658
1.672
1.996
2.007
2.018
2.028
2.038
2.052
3.111
3.128
3.146
3.164
3.291
3.308
3.325
3.342
3.410
3.436
3.446
3.453
3.471
3.487
3.531
3.549
3.567
3.584
4.141
4.151
4.176
4.186
7.156
7.173
7.191
7.209
7.244
7.262
7.282
7.691
7.699
7.705
7.713
7.722
7.817
7.827
7.835
7.841
7.848
3.04
4.11
1.01
1.09
1.03
1.03
2.03
1.04
1.00
5.11
2.03
1.96
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
12.472
12.711
20.563
24.529
34.751
39.336
39.504
41.776
76.704
77.023
77.340
123.140
125.957
126.506
128.594
132.092
133.864
140.318
168.173
169.093
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2012
S19
(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (1)
Under N2, phtalimide 9 (61 mg, 0.16 mmol, 1 equiv) was diluted in
anhydrous toluene (2 mL) and ethanolamine (98 µL, 10 equiv) was
added. The reaction mixture was heated to 100 °C for 3 h, cooled down
to rt, and quenched with 20% NaCl (3 mL). The aqueous layer was extracted with toluene (2
× 3 mL). The combined organic layers were washed with 20% NaCl (2 × 3 mL) and extracted
with 1 M HCl (2 × 3 mL). The organic phase was discarded. The combined aqueous layers
were basified with 20% NaOH and extracted with toluene (3 × 3 mL). The combined organic
layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure to give compound 1 as an oil (36 mg, 89%).
Spectral data obtained for 1 are in agreement with those previously reported in the literature.8
Rf 0.10 (CH2Cl2/MeOH 9:1).
1H NMR (CDCl3): δ 0.66 (3H, t, J = 7.3 Hz), 1.09 (3H, t, J = 7.6 Hz), 1.15 (1H, dd, J = 8.3
Hz, J = 5.2 Hz), 1.30–1.34 (1H, m), 1.56 (2H, brs), 1.72–1.77 (1H, m), 2.65 (1H, dd, J = 13.0
Hz, J = 7.2 Hz), 2.78 (1H, dd, J = 13.0 Hz, J = 7.2 Hz), 3.11–3.25 (2H, m), 3.44–3.55 (2H,
m), 7.10–7.30 (5H, m).
13C NMR (CDCl3): δ 12.3, 12.7, 19.4, 29.5, 34.7, 39.2, 41.6, 43.6, 125.9 (2C), 126.3, 128.6
(2C), 141.1, 170.1.
IR (neat): 3421, 3364, 1626, 1429 cm-1.
Chiral HPLC:
Enantiomeric excess was measured on N-acetyl-levomilnacipran which was obtained by
acetylation of levomilnacipran 1. Daicel OJ-R 150 × 4.6 mm, H2O/MeOH 5:5, flow rate: 1
mL min-1, detection at 200 nm, tmajor = 7.0 min, tminor = 8.9 min, 88% ee.
[α]20 D –88.3 (c 1.0, CHCl3).
MS (ES+): 247 [M+H]+.
8 Adv. Synth. Catal. 2001, 343, 299.
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2012
S20
9.5 9.0 8.5 8.0 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 ppm
1.155
1.168
1.305
1.321
1.334
1.560
1.722
1.739
1.743
1.760
2.624
2.642
2.656
2.674
2.759
2.776
2.791
2.809
3.118
3.135
3.153
3.171
3.190
3.208
3.224
3.242
3.440
3.458
3.475
3.492
3.511
3.529
3.547
7.169
7.191
7.211
7.247
7.265
7.285
3.00
2.95
1.09
1.03
2.19
1.03
1.01
1.00
2.04
2.04
5.09
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
12.332
12.741
19.393
29.532
34.758
39.181
41.578
43.597
76.680
76.999
77.316
125.924
126.299
128.571
141.063
170.019
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S21
(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide
hydrochloride (1·HCl)
To a solution of 1 (18 mg, 0.073 mmol) in Et2O (2 mL), was added a
saturated solution of HCl in Et2O (0.5 mL). The hydrochloride of 1
precipitated out spontaneously. The reaction mixture was further
stirred for 15 min, decanted, and the supernatant was discarded. The solid was suspended in
Et2O (2 mL), stirred for 15 min, decanted, and the supernatant was discarded. The washing
step was repeated twice. Finally, the solid was collected and dried under vaccum overnight to
give compound 1·HCl as a white solid (20 mg, 97 %).
Analytical data obtained for 1·HCl are in agreement with those previously reported in the
literature.9
1H NMR (CDCl3): δ 0.90 (3H, t, J = 7.0 Hz), 1.09–1.31 (4H, m), 1.62–1.80 (1H, m), 1.82–
1.87 (1H, m), 2.35–2.53 (1H, m), 3.27–3.47 (4H, m), 3.72–3.84 (1H, m), 7.15–7.30 (5H, m),
8.83 (3H, brs).
13C NMR (CDCl3): δ 12.2, 13.0, 17.9, 25.5, 34.6, 39.6, 42.0, 43.1, 125.6 (2C), 127.3, 128.9
(2C), 138.1, 170.7.
IR (KBr): 3409, 1615, 1467 cm-1.
[α]20 D +72.5 (c 0.70, CHCl3); (lit.,10
[α]20 D +72.8 (c 0.95, CHCl3), 96% ee).
9 J. Med. Chem. 1995, 38, 2967. 10 Tetrahedron Lett. 1996, 37, 641.
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2012
S22
9.5 9.0 8.5 8.0 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 ppm
0.884
0.901
0.919
1.092
1.109
1.127
1.708
1.751
1.834
1.847
1.869
2.449
3.274
3.291
3.307
3.325
3.337
3.354
3.371
3.385
3.401
3.416
3.433
3.451
3.469
3.744
7.157
7.176
7.196
7.215
7.232
7.263
7.269
7.289
7.306
8.829
3.10
3.97
1.35
0.95
0.97
1.02
4.06
1.00
1.93
1.08
1.78
2.78
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
12.192
12.977
17.931
25.491
34.634
39.590
41.960
43.127
76.622
76.940
77.146
77.257
125.643
127.253
128.941
138.131
170.696
Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2012