3682 J . Org. Chem., Vol. 64, No. 10, 1999
Grepioni et al.
P r ep a r a t ion of N,N′-Di-[(S)-1-p h en ylet h yl)]-(1R,2R,-
4S,5S)-1,2-d ia m in o-4,5-d im eth ylcycloh exa n e 11a . To the
solution of N,N′-di-[(S)-1-phenylethyl)]-4(S),5(S)-diaminoocta-
1,7-diene 10 (0.174 g, 0.5 mmol) in anhydrous Et2O in a dry
apparatus under an Ar atmosphere was added n-BuMgCl (2
M in Et2O, 1.25 mL, 2.5 mmol) dropwise with stirring. After
30 min, Cp2ZrCl2 (0.015 g, 0.051 mmol) was added and the
mixture was stirred for 18 h at room temperature; then water
was added and the organic phase was extracted with Et2O,
dried with Na2SO4, and concentrated to give 11a -c as an oil
(0.160 g, 91%). GC-MS analysis of the crude product allowed
for the determination of an 82:5:13 ratio of three diastereomers
in order of increasing retention time. The product was dis-
solved in MeOH (2 mL); then 37% HCl (1 mmol) was added to
the solution cooled at 0-5 °C. Water was eliminated by adding
benzene and concentrating at reduced pressure, and repeating
this operation two times. The white solid obtained was washed
with anhydrous cold CH2Cl2; then the residue was crystallized
from MeOH to obtain pure 11a (HCl)2 (0.133 g): mp 252 °C
(dec); [R]20D -30 (c 1, MeOH); 1H NMR (200 MHz, D2O) δ 7.37
and 7.16 (2 m, 10 H), 4.30 (q, 2 H), 3.02 (m, 2 H), 1.95-1.15
(m, 6 H), 1.43 (d, J ) 6.7 Hz, 6 H), 0.81 (d, J ) 6.0 Hz, 6 H)
ppm.
-78 °C in an Ar atmosphere, and stirring was continued for 1
h. Then the solution of the diamine 7 (0.350 g, 1 mmol) in THF
(5 mL) was dropwise added, the cooling bath was removed,
and stirring was continued while the temperature was allowed
to reach 0 °C during 2 h. The reaction mixture was quenched
by adding MeOH (5 mL) and aqueous NaHCO3 (10 mL), the
organic phase was extracted with Et2O, and the collected Et2O
layers were dried with Na2SO4 and concentrated to leave an
oil. GC-MS analysis showed that it was a mixture of diaster-
eomers 11a -c in a ratio of 6:16:78, in order of elution. The
product was chromatographed on a SiO2 column eluting with
cyclohexanes-ethyl acetate 3:1 to give 11c (0.200 g, 56%,
1
>98% pure): [R]20 -146 (c 0.7, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 7.25 (m, 10 H), 3.85 (m, 2 H), 2.10-1.60 (m, 8 H),
1.35 and 1.33 (2 d, 6 H, J ) 6.9 Hz, 1.08 and 0.86 (2 m, 2 H),
0.79 and 0.64 (2 d, J ) 6.9 Hz, 6 H) ppm. Anal. Found: C,
82.30; H, 9.76; N, 7.94. C24H34N2 required: C, 82.23; H, 9.78;
N, 7.99.
The dipicrate of 11c was prepared and recrystallized from
methanol, but the crystals were not suitable for X-ray-
analysis: 1H NMR (300 MHz, CDCl3-D2O) δ 9.03 (s, 4 H,
picrate), 7.30 (m, 10 H), 4.51 (q, 2 H), 3.51 (s, 3 H, CH3OH),
3.31 (m, 2 H), 2.18-1.83 (m, 6 H), 1.66 and 1.62 (2 d,
J ) 6.6 Hz, 6 H), 0.87 and 0.50 (2 d, J ) 6.0 and 7.5 Hz, 6 H)
ppm.
The salt was treated with 1 M NaOH (2 mL), and the free
base was extracted with Et2O; then the collected Et2O layers
were dried with Na2SO4 and concentrated to leave the pure
P r ep a r a t ion of N,N′-Di(4-t olu en esu lfon yl)-(1R,2R,-
4R,5R)-1,2-d ia m in o-4,5-d im eth ylcycloh exa n e 13. A Parr
apparatus was filled with the salt 11a (HCl)2 (0.45 g, 1.06
mmol), MeOH (35 mL), and Pd(OH)2/C (0.150 g) and then
submitted to a pressure of 48 psi of H2 for 36 h. The solution
was filtered through a small pad of Celite and then concen-
trated to leave the crude primary diamine dihydrochloride 12
as a glassy solid, which was rinsed with CH2Cl2 and dried at
reduced pressure: 0.161 g, 75%; mp 220 °C (dec); [R]25D -18.7
diamine 11a as an oil (0.105 g, 3 mmol, 60%): [R]20 -82.3 (c
D
1
1.1, CHCl3); H NMR (300 MHz, CDCl3) δ 7.37-7.20 (m, 10
H), 3.75 (q, 2 H), 2.32 (m, 2 H), 1.6 (broad, 2 H), 1.50-1.30
(m, 6 H), 1.27 (d, J ) 6.6 Hz, 6 H), 0.85 (d, J ) 6.0 Hz, 6 H)
ppm; MS, m/z (relative intensity) 105 (100, PhCHCH3), 120
(36, PhCHMeNH), 245 (7, M+ - PhCHCH3). Anal. Found: C,
82.30; H, 9.74; N, 7.96. C24H34N2 required: C, 82.23; H, 9.78;
N, 7.99.
1
The dipicrate of 11a was prepared by adding 11a (0.455 g,
1.3 mmol) to a solution of picric acid (0.595 g, 2.6 mmol) in
Et2O (60 mL). The precipitate that was formed immediately
was recrystallized from methanol to obtain crystals of 11a -
(C6H3N3O7)2(CH3OH) suitable for X-ray analysis: mp 159-
(c 0.65, CH3OH); H NMR (300 MHz, CDCl3) δ 3.55 (m, 2 H),
1.78, 1.60, and 1.37 (3 m, 6 H), 0.86 (d, J ) 6.0 Hz, 6 H) ppm.
The solid (0.107 g, 0.5 mmol) was suspended in CH2Cl2 (5
mL), the mixture was cooled at 0-5 °C with an ice bath, and
then ethyldiisopropylamine (1.06 mL, 6.3 mmol) was added.
After stirring for 15 min at 25 °C, the mixture was again cooled
to 0 °C, and then 4-toluenesulfonyl chloride (0.230 g, 1.2 mmol)
was added. After stirring for a further 2 h, 2 N HCl (5 mL)
was added and the organic phase was extracted with Et2O.
The collected ethereal layers were washed with brine, dried
with Na2SO4, and concentrated to leave the diamide 13 as a
white solid, which was crystallyzed two times from CH2Cl2-
1
160 °C; H NMR (300 MHz, CDCl3-D2O) spectroscopy δ 9.02
(s, 4 H, picrate), 7.30 (m, 10 H), 4.54 (q, 2 H), 3.52 (s, 3 H,
CH3OH), 3.49 (m, 2 H), 1.67-2.16 (m, 6 H), 1.63 (d, J ) 6.6
Hz, 6 H), 0.70 (d, J ) 6.9 Hz, 6 H) ppm.
Cr ysta l Str u ctu r e Ch a r a cter iza tion of 11a (C6H3N3O7)2-
(CH3OH). All X-ray diffraction data collections were carried
out on a NONIUS CAD-4 diffractometer equipped with an
Oxford Cryostream liquid-N2 device. Diffraction data were
corrected for absorption by azimuthal scanning of high-ø
reflections. SHELX86 (Sheldrick, G. M. Acta Crystallogr. 1990,
146, 467) and SHELXL92 (Sheldrick, G. M. SHELXL92,
Program for Crystal Structure Determination; University of
Goettingen: Goettingen, Germany, 1992) were used for struc-
ture solution and refinement based on F2. SCHAKAL97
(Keller, E. SCHAKAL97, Graphical Representation of Molec-
ular Models; University of Freiburg: Germany, 1997) was used
for the graphical representation of the results. Mo KR radia-
tion: λ ) 0.71069 Å, graphite monochromated , T ) 273(2) K.
All non-H atoms were refined anisotropically. The hydrogen
atoms were added in calculated positions and refined aniso-
tropically.
Crystal data: orthorombic, space group P212121, colorless
crystals, a ) 10.520(8), b ) 13.151(6), and c ) 29.43(2) Å, V )
4072(5) Å3, Z ) 4, dc ) 1.368 g cm-3, F(000) ) 1760, µ ) 0.108
mm-1, θ range 3.0-23.0°, 3233 reflections measured, 3197 of
which were independent, refinement on F2 for 494 parameters,
wR (F2, all reflections) ) 0.2524, R1(I > 2σI) ) 0.0758, S )
1.027.
cyclohexane: 0.130 g (58%); mp 205-206 °C; [R]20 +65.8 (c
D
0.8, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J ) 7.8
Hz, 4 H), 7.32 (d, J ) 8.1 Hz, 4 H), 4.71 (d, J ) 5.7 Hz, 2 H),
3.37 (m, 2 H), 2.45 (s, 6 H), 1.65-1.10 (m, 6 H), 0.82 (d, J )
5.4 Hz, 6 H) ppm. Anal. Found: C, 63.17; H, 7.22; N, 6.66.
C
22H30N2O4S2 required: C, 63.14; H, 7.23; N, 6.69.
P r ep a r a tion of Am in a ls 14 a n d 15c fr om th e Secon d -
a r y Dia m in es 10 a n d 15c. Gen er a l P r oced u r e. Paraform-
aldehyde (0.100 g, 4 mmol), p-TsOH-H2O (0.010 g), and
MgSO4 (0.5 g) were added to the solution of diamine 11c (0.070
g, 0.2 mmol) in anhydrous CH2Cl2 (5 mL). The mixture was
magnetically stirred at rt for 48 h and then filtered on Celite.
The solution was washed with a saturated NaHCO3 solution,
dried over MgSO4, and concentrated to leave the compound
15c in quantitative yield (0.072 g): [R]25D -42.5 (c 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.35-7.19 (m, 10 H), 3.88 and
3.85 (2 q, 2 H), 3.50 (s, 2 H), 2.45 and 2.32 (2 m, 2 H), 2.04-
1.68 (m, 4 H), 1.50 (m, 1 H), 1.37 (d, J ) 6.9 Hz), 1.27 (m, 1
H), 0.93 and 0.90 (2 d, J ) 6.6 and 7.5 Hz, 6 H) ppm; MS, m/z
(relative intensity) 105 (100, PhCHCH3), 361 (45, M+ - 1), 362
(18, M+). Anal. Found: C, 82.78; H, 9.48; N, 7.70. C25H34N2
required: C, 82.82; H, 9.45; N, 7.73.
P r ep a r a t ion of Am in a ls 15a -c fr om Am in a l 14. The
procedure previously described for the preparation of diamine
11a was followed, but 3 equiv of n-BuMgCl was used.
P r ep a r a t ion of N,N′-Di-[(S)-1-p h en ylet h yl)]-(1R,2R,-
4R,5S)-1,2-d ia m in o-4,5-d im eth ylcycloh exa n e 11c. A solu-
tion of Cp2ZrBu2 was prepared by adding dropwise n-BuLi (1.6
M in hexane, 5 mL, 8 mmol) to the stirred solution of Cp2-
ZrCl2 (1.16 g, 4 mmol) in anhydrous THF (10 mL), cooled to
1,3-Di[(S)-1-p h en yleth yl]-4(R),5(R)-d i(2-p r op en yl)im i-
1
d a zolid in e 14 (100%): [R]25 -33.1 (c 0.8, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 7.20-7.06 (m, 10 H), 5.81-5.63 (m, 2 H),
5.05-4.92 (m, 4 H), 3.76 (m, 2 H), 3.36 (s, 2 H), 2.76 (m, 2 H),
2.24 and 2.14 (2 m, 4 H), 1.60 (s, ca. 1 H, NH, probably due to
incorporated H2O), 1.30 (m, 6 H) ppm; MS, m/z (relative
intensity) 105 (100, PhCHCH3), 319 (17), 69 (11), 79 (10), 173