2726
H. Schramm, J. Christoffers / Tetrahedron: Asymmetry 20 (2009) 2724–2727
mo-Fisher). IR spectra were recorded on a Bruker Tensor 27 spec-
trometer equipped with a ‘GoldenGate’ diamond-ATR unit. Ele-
mental analyses were measured with a Euro EA-CHNS from
HEKAtech and optical rotations with a Perkin Elmer polarimeter
343. Piperidone 1 was prepared as reported earlier.4 All other start-
ing materials were commercially available.
(m, br), 1603 (m), 1496 (s), 1454 (s), 1351 (m), 1100 (m), 1074
(m), 735 (vs), 699 (vs) cmꢁ1. MS (EI, 70 eV): m/z (%) = 266 (8)
[M+], 249 (59), 223 (13), 175 (16), 146 (17), 132 (20), 119 (47),
104 (41), 91 (100), 77 (8), 65 (17). HRMS (EI, 70 eV): calcd
266.1783 (for C18H22N2), found 266.1774 [M+].
4.2.3. N-(1-Benzyl-3-phenyl-4-piperidinyl)-(1S)-
4.2. Procedures
camphorsulfonamides 5a and 5b
At first, NEt3 (0.4 mL, 2.9 mmol) was dropwise added to a solu-
tion of the racemic amine 3 (400 mg, 1.50 mmol) in DCM (3 mL).
(1S)-(+)-Camphor-10-sulfonylchloride 4 (0.75 g, 3.0 mmol) was
added portionwise at 0 °C and the resulting mixture was stirred
at ambient temperature for 1 h. Next, H2O (5 ml) was added and
the organic layer was separated. Subsequently, the aqueous layer
was extracted with DCM (3 ꢂ 3 mL) and the combined organic lay-
ers were evaporated. After purification by chromatography [hex-
ane/ethyl acetate = 1:1, Rf (hexane/ethyl acetate 2:1) = 0.11], a
mixture (ratio 1:1) of compounds 5a and 5b (0.44 g, 0.91 mmol,
60%) was yielded as a colorless solid, mp 60 °C. Repeated chroma-
tography gave pure diastereoisomer 5a as the less polar of both
compounds. The procedure was applied to both the enantiomers
of amine 3 as well. The following analytical data are given for
the two pure diastereoisomers.
4.2.1. rac-1-Benzyl-4-(hydroxyimino)-3-phenylpiperidine 2
At first, NaOAc (2.90 g, 35.4 mmol) and NH2OHꢀHCl (2.46 g,
35.4 mmol) were added to a solution of 4-piperidone 1 (0.93 g,
3.5 mmol) in EtOH/H2O 1:1 (30 mL). The solution was stirred at re-
flux for 4 h. Next, H2O (15 mL) and a saturated solution of Na2CO3
(ca. 40 mL) were added until pH 10. After the addition of DCM
(30 mL), the layers were separated. The aqueous phase was ex-
tracted with DCM (3 ꢂ 30 mL). The combined organic layers were
dried (MgSO4), filtered, and evaporated. Compound 2 (0.98 g,
3.5 mmol, 98%) was yielded as a colorless solid and was used with-
out further purification, mp 39 °C. The 1H NMR shows a doubled
signal set (isomers A and B, ratio 3:1), because of two double bond
configurations. 1H NMR (CDCl3, 500 MHz): d = 2.15–2.22 (m, 2H;
isomer B), 2.41 (dd, J = 12.0 Hz, J = 4.4 Hz, 1H; isomer B), 2.49–
2.55 (m, 2H; isomer A), 2.71–2.74 (m, 1H; isomer A), 2.78–2.90
(m, 4H; 3H of isomer A, 1H of isomer B), 3.03–3.06 (m, 1H; isomer
B), 3.32–3.34 (m, 1H; isomer B), 3.54 (s, 2H; isomer B), 3.58 (s, 2H;
isomer A), 3.67 (dd, J = 8.1 Hz, J = 4.7 Hz, 1H; isomer A), 4.65 (d,
J = 3.5 Hz, 1H; isomer B), 7.19–7.33 (m, 18H; 10H of isomer A, 8H
of isomer B), 7.55 (d, J = 7.6 Hz, 2H; isomer B), 8.25 (s, br, 2H)
ppm. 13C{1H} NMR (CDCl3, 125 MHz), isomer A: d = 23.47 (CH2),
46.89 (CH), 52.41 (CH2), 58.65 (CH2), 62.59 (CH2), 126.72 (CH),
127.21 (CH), 128.17 (2CH), 128.25 (2CH), 128.62 (2CH), 129.14
(2CH), 137.71 (C), 139.10 (C), 159.21 (C) ppm; isomer B:
d = 29.19 (CH2), 37.89 (CH), 53.68 (CH2), 55.98 (CH2), 62.77 (CH2),
126.28 (CH), 127.15 (CH), 128.12 (2CH), 128.21 (2CH), 128.54
(2CH), 129.06 (2CH), 138.16 (C), 140.25 (C), 158.62 (C) ppm. IR
(ATR): 1/k = 3261 (s, br), 3061 (w), 3027 (w), 2906 (w), 2804 (w),
1656 (w), 1601 (w), 1491 (m), 1452 (m), 1350 (w), 1115 (m),
1009 (m), 948 (s, br), 736 (s), 696 (vs) cm–1. MS (EI, 70 eV): m/z
(%) = 280 (100) [M+], 263 (9), 202 (3), 189 (30), 171 (4), 143 (11),
116 (14), 91 (79), 65 (6). Calcd for C18H20N2O (280.36): C, 77.11;
H, 7.19; N, 9.99. Found: C, 76.74; H, 7.16; N, 9.78. HRMS (EI,
70 eV): calcd 280.1576 (für C18H20N2O), found 280.1576 [M+].
4.2.4. (3R,4S)-(ꢁ)-N-(1-Benzyl-3-phenyl-4-piperidinyl)-(1S)-
camphorsulfonamide 5a
1H NMR (CDCl3, 300 MHz): d = 0.67 (s, 3H), 0.91 (s, 3H), 1.31 (ddd,
J = 3.6 Hz, J = 9.2 Hz, J = 12.6 Hz, 1H), 1.65 (ddd, J = 4.7 Hz, J = 9.4 Hz,
J = 14.1 Hz, 1H), 1.84 (d, J = 18.4 Hz, 1H), 1.93 (ddt, J = 4.3 Hz,
J = 12.0 Hz, J = 15.6 Hz, 1H), 1.97–2.02 (m, 3H), 2.17 (t, J = 11.7 Hz,
1H), 2.28 (dt, J = 3.7 Hz, J = 18.3 Hz, 2H), 2.44–2.58 (m, 1H), 2.58–
2.71 (m, 2H), 2.71–2.81 (m, 1H), 2.86 (d, J = 9.4 Hz, 1H), 3.19–3.25
(m, 1H), 3.56 (A-part of an AB-system, J = 13.1 Hz, 1H), 3.62 (B-part
of an AB-system, J = 13.1 Hz, 1H), 3.90–3.97 (m, 1H), 4.88 (s, br.,
1H; NH), 7.16–7.26 (m, 2H), 7.26–7.47 (m, 8H) ppm. 13C{1H} NMR
(CDCl3, 125 MHz): d = 19.46 (CH3), 19.87 (CH3), 26.63 (CH2), 26.80
(CH2), 32.44 (CH2), 42.59 (CH), 42.61 (CH2), 44.58 (CH), 48.00 (C),
49.08 (CH2), 49.39 (CH2), 50.57 (CH2), 53.61 (CH), 58.53 (C), 63.23
(CH2), 126.93 (CH), 127.05 (CH), 128.22 (3CH), 128.39 (2CH),
128.55 (CH), 128.98 (2CH), 138.01 (C), 140.57 (C), 215.19 (C) ppm.
IR (ATR): 1/k = 3291 (m, br), 3029 (w), 2953 (m, br), 1745 (vs),
1455 (m), 1321 (s), 1443 (vs), 1055 (m), 1007 (m), 912 (m), 757 (s),
740 (s), 701 (vs) cmꢁ1. MS (ESI): m/z (%) = 481 (100) [M+H+]. HRMS
(ESI): calcd 480.2447 (for C28H36N2O3S), found 480.2446 [M+].
4.2.2. rac-4-Amino-1-benzyl-3-phenylpiperidine 3
½
a 2D2
ꢃ
¼ ꢁ23 (c 0.31, MeOH).
Under an N2-atmosphere, LiAlH4 (4.97 g, 131 mmol) was added
portionwise to a solution of oxime 2 (3.67 g, 13.1 mmol) in abs.
THF (70 ml) at 0 °C. The mixture was stirred for 16 h at ambient
temperature. Then ethyl acetate (60 ml) and H2O (50 mL) were
dropwise added at 0 °C and the mixture was stirred for 30 min.
After filtration and extraction of the aqueous layer with DCM
(3 ꢂ 60 mL), the residue was washed with DCM (500 mL). The res-
idue was treated with THF (60 mL) and refluxed for 30 min. After
filtration, the combined organic layers were dried (MgSO4), fil-
tered, and evaporated. Chromatography (SiO2, DCM/MeOH 10:1,
Rf = 0.26) yielded racemic compound cis-3 as a yellow oil (2.10 g,
7.87 mmol, 60%). 1H NMR (CDCl3, 500 MHz): d = 0.83 (s, br, 2H),
1.66–1.74 (m, 1H), 1.93–2.00 (m, 1H), 2.50–2.56 (m, 2H), 2.71
(dd, J = 3.3 Hz, J = 10.9 Hz, 1H), 2.78 (t, J = 10.8 Hz, 1H), 3.05–3.09
(m, 1H), 3.22–3.23 (m, 1H), 3.55 (A-part of an AB-system,
J = 13.1 Hz, 1H), 3.60 (B-part of an AB-system, J = 13.1 Hz, 1H),
7.19–7.36 (m, 10 H) ppm. 13C{1H} NMR (CDCl3, 125 MHz):
d = 32.72 (CH2), 46.38 (CH), 48.65 (CH2), 49.60 (CH), 52.31 (CH2),
63.47 (CH2), 126.34 (CH), 126.88 (CH), 128.15 (3CH), 128.19
(2CH), 128.38 (CH), 129.02 (2CH), 138.35 (C), 141.93 (C) ppm. IR
(ATR): 1/k = 3405 (m), 3062 (w), 3028 (w), 2917 (m, br), 2811
4.2.5. (3S,4R)-(+)-N-(1-Benzyl-3-phenyl-4-piperidinyl)-(1S)-
camphorsulfonamide 5b
1H NMR (CDCl3, 300 MHz): d = 0.72 (s, 3H), 0.94 (s, 3H), 1.33
(ddd, J = 3.4 Hz, J = 8.9 Hz, J = 12.4 Hz, 1H), 1.59 (J = 4.5 Hz,
J = 9.3 Hz, J = 13.8 Hz, 1H), 1.84 (d, J = 18.5 Hz, 1H), 1.91–2.00 (m,
ddt, 3H), 2.03 (t, J = 4.6 Hz, 1H), 2.12–2.43 (m, 3H), 2.47–2.74 (m,
3H), 2.81 (dd, J = 11.5 Hz, J = 2.9 Hz, 1H), 2.95 (d, J = 14.7 Hz, 1H),
3.19–3.25 (m, 1H), 3.53 (A-part of an AB-system, J = 13.1 Hz, 1H),
3.60 (B-part of an AB-system, J = 13.1 Hz, 1H), 3.84–3.91 (m, 1H),
4.59–4.74 (m, 1H), 7.16–7.38 (m, 8H), 7.41–7.49 (m, 1H) ppm.
13C{1H} NMR (CDCl3, 125 MHz) d = 19.49 (CH3), 19.69 (CH3),
25.24 (CH2), 26.78 (CH2), 31.49 (CH2), 42.54 (CH), 42.56 (CH2),
44.77 (CH), 47.99 (C), 49.27 (CH2), 49.95 (CH2), 50.59 (CH2),
53.38 (CH), 58.24 (C), 63.19 (CH2), 126.87 (CH), 127.02 (CH),
128.19 (CH), 128.25 (2 CH), 128.60 (CH), 128.94 (4 CH), 138.05
(C), 140.33 (C), 215.08 (C) ppm. ½a D23
¼ þ24 (c 1.55, MeOH).
ꢃ
4.2.6. Salt precipitation with mandelic acids
-(+)-Mandelic acid (S)-6 (120 mg, 0.79 mmol) was dissolved in
ethyl acetate (1 mL) at 80 °C. This hot solution was dropwise added
L