ꢀ
J. Gonzꢀalez-Sabın et al. / Tetrahedron: Asymmetry 15 (2004) 1335–1341
1339
J ¼ 6:5 Hz, CH3), 1.17 (m, 4H), 1.52–1.72 (m, 3H), 2.03
(m, 1H), 2.11 (s, 3H, N–CH3), 2.25 (m, 1H), 2.82 (hept,
1H, J ¼ 6:5 Hz, N–CH), 3.20 (dt, 1H, J ¼ 4:6 and
9.8 Hz, CH–OH), 4.04 (s, 1H, OH); 13C NMR
(75.5 MHz): d 20.12 (CH3), 20.60 (CH3), 23.97 (CH2),
25.23 (CH2), 25.48 (CH2), 30.51 (CH3), 32.90 (CH2),
52.74 (CH), 66.02 (CH), 68.70 (CH); MS (ESIþ) m=z
(rel. intensity): 172.1 [(MþH)þ, 100]. Anal. Calcd for
C10H21NO: C, 70.12; H, 12.36; N, 8.18. Found: C, 70.06;
H, 12.18; N, 8.35.
4.3.7. (1S,2S)-2-(4-Methoxycarbonylpiperidin-1-yl)-cy-
clohexanol (1S,2S)-7. Yield: 47%, mp 51–53 ꢁC.
20
½aꢂ ¼ þ44:0 (c 1.1, CHCl3) 95% ee. IR (KBr) 3491,
D
1
1729 cmꢁ1; H NMR (200 MHz): d 1.00–1.30 (m, 4H),
1.50–2.35 (m, 11H), 2.56–2.70 (m, 2H), 2.84 (dt, 1H,
J ¼ 11:7 and 3.5 Hz), 3.34 (dt, 1H, J ¼ 4:6 and 9.7 Hz),
3.65 (s, 3H, OCH3), 3.85 (br s, 1H, OH); 13C NMR
(50.3 MHz): d 21.84 (CH2), 23.64 (CH2), 25.11 (CH2),
28.40 (CH2), 28.62 (CH2), 32.85 (CH2), 40.89 (CH),
44.68 (CH2), 50.93 (CH2), 51.18 (CH3), 68.11 (CH),
70.21 (CH), 174.96 (C); MS (ESIþ) m=z (rel. intensity):
242.1 [(MþH)þ, 100], 264.1 [(MþNa)þ, 10]. Anal. Calcd
for C13H23NO3: C, 64.70; H, 9.61; N, 5.80. Found: C,
64.89; H, 9.52; N, 5.99.
4.3.3. (1S,2S)-2-(Pyrrolidin-1-yl)cyclohexanol (1S,2S)-3.
20
D
Yield: 44% ½aꢂ ¼ þ54:6 (c 0.80, CHCl3) 78% ee. Lit.13
25
for (1S,2S)-(þ)-3: ½aꢂ ¼ þ21:91 (c 1.02, CH2Cl2) 36%
D
1
ee. H NMR (200 MHz): d 1.17 (m, 4H), 1.68 (m, 7H),
2.05 (m, 1H), 2.30–2.70 (m, 5H), 3.29 (dt, 1H, J ¼ 4:5
and 10.0 Hz, CH–OH), 3.98 (br s, 1H, OH); 13C NMR
data were in agreement with the literature.13 MS (ESIþ)
m=z (rel. intensity): 170.1 [(MþH)þ, 100].
4.3.8.
(1S,2S)-2-(4-Formylpiperazin-1-yl)cyclohexanol
20
(1S,2S)-8. Yield: 58%, mp 56–58 ꢁC. ½aꢂ ¼ þ32:9
D
(c 0.93, CHCl3) 70% ee. IR (KBr) 3454, 1674 cmꢁ1; H
1
NMR (300 MHz): d 1.19 (m, 4H), 1.75 (m, 3H), 2.00–
2.50 (m, 4H), 2.69 (m, 2H), 3.20–3.70 (m, 6H including
OH), 7.99 (s, 1H); 13C NMR (75.5 MHz): d 22.14 (CH2),
23.60 (CH2), 25.00 (CH2), 32.85 (CH2), 40.12 (CH2),
45.82 (CH2), 47.54 (CH2), 48.78 (CH2), 68.19 (CH),
70.26 (CH), 160.36 (CH); MS (ESIþ) m=z (rel. intensity):
213.1 [(MþH)þ, 38], 235.1 [(MþNa)þ, 100]. Anal. Calcd
for C11H20N2O2: C, 62,23; H, 9,50; N, 13,20. Found: C,
62.05; H, 9.65; N, 13.36.
4.3.4. (1S,2S)-2-(Morpholin-4-yl)cyclohexanol (1S,2S)-4.
20
D
Yield: 52%. ½aꢂ ¼ þ53:6 (c 1.1, CHCl3) 74% ee. 1H
NMR (300 MHz): d 0.98 (m, 4H), 1.40–1.66 (m, 3H),
1.80–2.00 (m, 2H), 2.19 (m, 2H), 2.48 (m, 2H), 3.14 (dt,
1H, J ¼ 4:7 and 10.0 Hz, CH–OH), 3.47 (m, 4H, 2CH2–
O) 3.58 (br s, 1H, OH); 13C NMR data were in agree-
ment with the literature.12 MS (ESIþ) m=z (rel. inten-
sity): 186.1 (MþH)þ, 100], 208.1 [(MþNa)þ, 6].
4.3.9. (1R,2R)-2-(N-Benzyl-N-methylamino)cyclohexyl
20
D
acetate (1R,2R)-9. Yield: 36%. ½aꢂ ¼ þ2:0 (c 0.65,
CHCl3) >99% ee. IR (neat) 1733, 1243 cmꢁ1; H NMR
1
4.3.5. (1S,2S)-2-(4-Phenylpiperidin-1-yl)cyclohexanol
(1S,2S)-5. Yield: 49%. Hydrochloride salt of (1S,2S)-5:
(200 MHz): d 1.15–1.50 (m, 4H), 1.60–2.20 [m þ s,
4H þ 3H (CH3)], 2.23 (s, 3H, CH3), 2.62 (dt, 1H, J ¼ 3:8
and 10.8 Hz), AB system (dA 3.72, dB 3.61,
JA;B ¼ 13:5 Hz, 2H), 4.96 (dt, 1H, J ¼ 4:7 and 10.2 Hz,
CH–OAc), 7.15–7.40 (m, 5H, Ph); 13C NMR
(75.5 MHz): d 21.44 (CH3), 24.25 (CH2), 24.87 (CH2),
25.05 (CH2), 31.86 (CH2), 36.80 (CH3), 58.62 (CH2),
65.17 (CH), 72.40 (CH), 126.50 (CH), 127.97 (CH),
128.26 (CH), 140.32 (C), 170.45 (C); MS (ESIþ) m=z (rel.
intensity): Anal. Calcd for C16H23NO2: C, 73.53; H,
8.87; N, 5,36. Found: C, 73.42; H, 8.73; N, 5.48.
20
D
½aꢂ ¼ þ20:7 (c 1.4, EtOH) 95% ee. Lit.9 for (1R,2R)-
23
D
(ꢁ)-5xHCl: ½aꢂ ¼ ꢁ22:8 (c 1.4, EtOH) enantiopure.
1H NMR (300 MHz): d 1.17–1.42 (m, 4H), 1.60–2.00 (m,
7H), 2.17–2.31 (m, 3H), 2.51 (m, 1H), 2.77 (m, 2H), 2.97
(m, 1H), 3.44 (dt, 1H, J ¼ 4:6 and 9.6 Hz, CH–OH),
4.15 (br s, 1H, OH), 7.20–7.40 (m, 5H, Ph); 13C NMR
(75.5 MHz): d 22.06 (CH2), 23.95 (CH2), 25.46 (CH2),
33.11 (CH2), 33.81 (CH2), 34.20 (CH2), 42.83 (CH),
45.25 (CH2), 53.29 (CH2), 68.48 (CH), 70.46 (CH),
125.96 (CH), 126.65 (CH), 128.23 (CH), 146.13 (C); MS
(ESIþ) m=z (rel. intensity): 260.2 [(MþH)þ, 100.
4.3.10.
(1R,2R)-2-(N-Isopropyl-N-methylamino)cyclo-
20
4.3.6. (1S,2S)-2-(4-Phenyl-1,2,5,6-tetrahydropyridin-1-
yl)cyclohexanol (1S,2S)-6. Yield: 51%, mp 120–122 ꢁC.
hexyl acetate (1R,2R)-10. Yield: 33%. ½aꢂ ¼ ꢁ25:2 (c
D
0.80, CHCl3) 92% ee. IR (neat) 1733 cmꢁ1; H NMR
1
20
½aꢂ ¼ þ26:9 (c 1.1, CHCl3) 93% ee. IR (KBr) 3420,
(300 MHz): d 0.95 (d, 3H, J ¼ 6:0 Hz, CH3), 0.97 (d, 3H,
J ¼ 6:0 Hz, CH3), 1.10–1.40 (m, 4H), 1.60–1.80 (m, 3H),
1.90–2.05 [mþs, 1Hþ3H (CH3)], 2.15 (s, 3H, N–CH3),
2.50 (dt, 1H, J ¼ 3:6 and 10.6 Hz), 2.82 (hept, 1H,
J ¼ 6:5 Hz, N–CH), 4.74 (dt, 1H, J ¼ 4:6 and 10.1 Hz,
CH–OAc); 13C NMR (75.5 MHz): d 20.46 (CH3), 20.66
(CH3), 21.34 (CH3), 24.21 (CH2), 25.08 (CH2), 27.77
(CH2), 31.43 (CH3), 31.68 (CH2), 52.49 (CH), 62.24
(CH), 72.19 (CH), 170.34 (C); MS (ESIþ) m=z (rel.
intensity): 214.1 [(MþH)þ, 100], 172.1 [(C10H22NO)þ,
32]. Anal. Calcd for C12H23NO2: C, 67.57; H, 10.87; N,
6.57. Found: C, 67.80; H, 10.96; N, 6.44.
D
1
1647, 1071 cmꢁ1. H NMR (300 MHz): d 1.15–1.40 (m,
4H), 1.70–1.90 (m, 3H), 2.10–2.65 (m, 5H), 3.01 (m, 1H),
3.40–3.56 (m, 2H), 3.90 (br s, 1H, OH), 6.12 (t, 1H,
J ¼ 3:6 Hz), 7.20–7.45 (m, 5H, Ph); 13C NMR
(75.5 MHz): d 21.81 (CH2), 24.05 (CH2), 25.46 (CH2),
28.70 (CH2), 33.18 (CH2), 44.82 (CH2), 48.55 (CH2),
68.72 (CH), 69.31 (CH), 122.23 (CH), 124.66 (CH),
126.86 (CH), 128.19 (CH), 134.90 (C), 140.62 (C); MS
(ESIþ) m=z (rel. intensity): 258.1 [(MþH)þ, 100]. Anal.
Calcd for C17H23NO: C, 79,33; H, 9,01; N, 5,44. Found:
C, 79.55; H, 8.89; N, 5.67.