J. Christoffers et al. / Tetrahedron 57 (2001) 1765±1769
1767
silica gel (Type 60, 0.063±0.200 mm) using tert-butyl
methyl ether (MTB) and hexanes (PE) as solvents. 1H
NMR: Bruker AM 400 (400 MHz) and Bruker AC 200
(200 MHz). 13C NMR: Bruker AC 200 (50 MHz), assign-
ments were made using DEPT experiments. MS (EI, 70 eV):
Varian MAT 711 and MAT 955Q (high resolution). IR:
Nicolet Magna IR 750. Elemental analyses: Analytik Jena
Vario EL. Optical rotations: Perkin±Elmer polarimeter 341;
[a] values are given in 1021 deg cm2 g21. All starting
materials were commercially available. Dimethylamine
was purchased from Fluka. Spectroscopic data of 2 were
in agreement with the literature.16
added slowly to a mixture of rac-3 (859 mg, 6.04 mmol),
NEt3 (611 mg, 6.04 mmol) and CH2Cl2 (2 ml) at 08C. After
stirring for 18 h at ambient temperature impurities were
removed by chromatography of the mixture on SiO2 with
MTB. Finally, elution with MeOH (Rf0.38) yielded a
mixture of 4a and 4b as a yellowish solid (2.05 g,
5.61 mmol, 93%), mp 968C. IR (ATR): n3239, 2934,
2863, 1745, 1454, 1391, 1339, 1318, 1145, 1050 cm21
.
C18H32N2O3S (356.53): Anal. calcd C 60.64, H 9.05, N,
7.86; found C 60.25, H 9.04, N 7.96. Mol. mass calcd
356.2131, found 356.2134 (M1, HRMS).
4.1.5.
(S,S)-1-Amino-2-(dimethylamino)cyclohexane
4.1.1. (Rp,Rp)-2-Azidocyclohexanol. A mixture of oxirane
1 (30.1 g, 0.306 mol) and NaN3 (50.4 g, 0.775 mol) in H2O±
acetone (330 ml, 1:1) was heated to re¯ux for 17 h. Acetone
was removed under reduced pressure and the residue
extracted with MTB (3£160 ml) and CH2Cl2 (3£160 ml).
The combined extracts were washed with water (2£40 ml)
and dried (MgSO4). After ®ltration removal of the solvent
yielded the azido alcohol (40.0 g, 0.283 mol, 93%) as a
practically pure yellow oil, which was converted without
further puri®cation. 1H NMR (200 MHz, CDCl3):
d1.24±1.37 (m, 4H), 1.66±1.75 (m, 2H), 2.00±2.15 (m,
2H), 2.24 (s, 1H; OH), 3.11±3.23 (m, 1H), 3.32±3.43 (m,
1H) ppm.
1-N-(1S)-(10-camphorsulfonate) (4a). The mixture of 4a
and 4b was separated by chromatography (SiO2, MTB/
MeOH 1:1) to yield isomer 4a in a ®rst fraction (Rf0.27)
and subsequently 4b as the more polar diastereoisomer
20
20
(Rf0.15), both as colorless oils. [a]D 148, [a]578
20
20
20
150, [a]546 158, [a]436 1110, [a]365 1230 (c
1
8.2 in CHCl3). H NMR (400 MHz, CDCl3): d0.86 (s,
3H), 1.07 (s, 3H), 1.12±1.21 (m, 2H), 1.21±1.30 (m, 2H),
1.40 (ddd, J3.9, 9.3, 12.8 Hz, 1H), 1.67±1.69 (m, 1H),
1.76±1.83 (m, 3H), 1.90 (d, J18.4 Hz, 1H), 1.97±2.06
(m, 1H), 2.08 (t, J4.5 Hz, 1H), 2.10±2.26 (m, 1H), 2.19
(s, 6H), 2.34 (dt, J18.5, 4.3 Hz, 1H), 2.35±2.47 (m, 2H),
2.97 (d, J14.8 Hz, 1H), 3.91 (td, J10.3, 4.2 Hz, 1H), 3.57
(d, J14.8 Hz, 1H), 6.01 (s, br., 1H) ppm. 13C{1H} NMR
(50 MHz, CDCl3): d19.72 (CH3), 19.76 (CH3), 21.35
(CH2), 24.47 (CH2), 25.09 (CH2), 25.41 (CH2), 26.98
(CH2), 33.54 (CH2), 39.82 (CH3), 42.72 (CH2), 42.80
(CH), 48.10 (C), 51.11 (CH2), 54.31 (CH), 58.96 (C),
66.60 (CH), 215.69 (CvO) ppm.
4.1.2. 7-Azabicyclo[4.1.0]heptane (2). PPh3 (57.7 g,
0.220 mol) was added within 30 min to a solution of azido-
cyclohexanol (31.1 g, 0.220 mol) in MTB (250 ml), while
N2 evolved from the mixture. After heating to re¯ux for 16 h
the solvent was stripped through a Vigreux column (20 cm)
at 760 mm. Continued distillation under reduced pressure
(bp 458C at 14 mm) yielded the aziridine 2 (16.8 g,
0.173 mol, 79%) as a colorless liquid, which solidi®ed
after a few days at ambient temperature; 1H NMR
(200 MHz, CDCl3): d0.18 (s, br., 1H), 0.96±1.28 (m,
4H), 1.61±1.72 (m, 4H), 1.97±2.04 (m, 2H) ppm.
4.1.6.
(R,R)-1-Amino-2-(dimethylamino)cyclohexane
20
1-N-(1S)-(10-camphorsulfonate) (4b). [a]D 228,
20
20
20
20
[a]578 228, [a]546 230, [a]436 225, [a]365
1
152 (c 4.4 in CHCl3). H NMR (400 MHz, CDCl3): d
0.87 (s, 3H), 1.12 (s, 3H), 1.17±1.32 (m, 4H), 1.40 (ddd,
J3.8, 9.3, 12.3 Hz, 1H), 1.63±1.70 (m, 2H), 1.79±1.83 (m,
2H), 1.92 (d, J18.4 Hz, 1H), 1.98±2.05 (m, 1H), 2.08 (t,
J4.5 Hz, 1H), 2.11±2.25 (m, 1H), 2.21 (s, 6H), 2.36 (dt,
J18.7, 4.2 Hz, 1H), 2.37±2.44 (m, 1H), 2.53 (ddd, J4.0,
11.9, 14.7 Hz, 1H), 2.86 (d, J14.9 Hz, 1H), 3.18 (td,
J10.3, 4.2 Hz, 1H), 3.61 (d, J14.9 Hz, 1H), 5.88 (s,
br., 1H) ppm. 13C{1H} NMR (50 MHz, CDCl3): d19.79
(CH3), 20.04 (CH3), 21.06 (CH2), 24.24 (CH2), 25.07
(2CH2), 26.88 (CH2), 32.84 (CH2), 39.80 (CH3), 42.63
(CH2), 42.71 (CH), 47.78 (C), 50.83 (CH2), 54.17 (CH),
58.62 (C), 66.25 (CH), 215.34 (CvO) ppm.
4.1.3. (Rp,Rp)-1-Amino-2-(dimethylamino)cyclohexane
(rac-3). CF3CO2H (3.37 g, 29.7 mmol) was dropwise
added to aziridine 2 (57.7 g, 594 mmol). At about 2108C
HNMe2 (134 g, 2.97 mol) was added and the resulting
mixture heated to 1408C for 20 h in an autoclave. After
the excess of HNMe2 evaporated at ambient temperature
the mixture was submitted to distillation through a 25 cm
Vigreux column at 14 mm yielding the diamine rac-3 (bp
788C, 14 mm) as a colorless, hygroscopic liquid (36.8 g,
259 mmol, 44%). IR (ATR): n3352, 3213, 2927, 2856,
2823, 2775, 1667, 1449 cm21
.
1H NMR (200 MHz,
CDCl3): d0.95±1.20 (m, 4H), 1.56±1.74 (m, 3H), 1.64
(s, 2H), 1.83±1.96 (m, 1H), 1.95 (td, J10.3, 3.3 Hz, 1H),
2.17 (s, 6H), 2.50 (td, J10.1, 4.2 Hz, 1H) ppm. 13C{1H}
NMR (50 MHz, CDCl3): d20.33 (CH2), 24.76 (CH2),
25.25 (CH2), 34.56 (CH2), 39.84 (CH3), 51.03 (CH), 69.30
(CH) ppm. MS (EI, 70 eV), m/z (%): 142 (50) [M1], 125
(19), 124 (21), 97 (80), 84 (100), 58 (77), 56 (95). C8H18N2
(142.24): Mol. mass calcd 142.1470, found 142.1470
(HRMS).
4.1.7. (R,R)-1-Ammonium-2-(dimethylammonium)cyclo-
hexane mono-l-tartrate (5). At 708C a solution of l-(1)-
tartaric acid (12.0 g, 80.0 mmol) in EtOH (20 ml) was added
to a stirred solution of rac-3 (22.7 g, 160 mmol) in EtOH
(10 ml). After cooling to 238C the mixture was further
stirred for 16 h. The precipitate was collected on a glass
frit, washed with MTB and dried in high vacuum to yield
the tartrate 5 as a colorless powder (3.50 g, 12.0 mmol,
14%), mp 1608C. From the supernatant the remaining
racemic 3 can be almost quantitatively recovered after
4.1.4. (Rp,Rp)-1-Amino-2-(dimethylamino)cyclohexane
1-N-(1S)-(10-camphorsulfonate) (4a and 4b). (1S)-(1)-
10-Camphorsulfonyl chloride (1.51 g, 6.04 mmol) was
extraction with aqueous KOH and MTB. [a]D20113.7,
20
20
20
[a]578 114.1,
20
[a]546 116.0,
[a]436 125.7,
[a]365 136.2 (c 4.25 in H2O). IR (ATR): n3367,