V. M. Foley et al. / Tetrahedron: Asymmetry 27 (2016) 1160–1167
1165
product which was purified by column chromatography (DCM
d, J = 6.7 Hz), 0.99–1.99 (8H, m), 1.30–1.54 (6H, m), 1.58–1.75
(4H, m), 2.17 (6H, s), 2.30–2.48 (6H, m) ppm. 13C NMR
(75.5 MHz, CDCl3): d 22.7 (4C), 25.7 (2C), 26.0 (2C), 26.4 (2C),
28.0 (2C), 36.6 (2C), 36.9 (2C), 54.7 (2C), 63.3 (2C) ppm. HRMS
(ESI) m/z calcd for C20H43N2 [M+H]+: 311.3426, found 311.3419.
with 5% MeOH and 0.5% NEt3) to yield (S,S)-8 as a pale yellow oil
(1.02 g, 50%).
[a] :
20 = +19.5 (c 0.5, CHCl3). IR (NaCl) mmax
D
2951–2788, 1467, 1364 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 0.88
(18H, s), 1.02–1.27 (8H, m), 1.32–1.50 (4H, m), 1.63–1.84 (4H,
m), 2.25 (6H, s), 2.34–2.56 (6H, m) ppm. 13C NMR (75.5 MHz,
CDCl3): d 23.9 (2C), 26.0 (2C), 26.1 (2C), 29.6 (6C), 30.4 (2C), 36.8
(2C), 42.2 (2C), 55.6 (2C), 63.4 (2C) ppm. HRMS (ESI) m/z calcd
for C22H47N2 [M+H]+: 339.3739, found 339.3737.
4.2.8. (4aS,12aS)-5,12-Bis(3,3-dimethylbutyl)-1,2,3,4,4a,5,6,11,
12,12a-decahydrodibenzo[b,f][1,4]diazocine, (S,S)-11
A solution of t-butylacetyl chloride (1.51 mL, 10.9 mmol) in
DCM (6 mL) was added dropwise to a stirred biphasic mixture of
4.2.5. (1R,2R)-N1,N2-Bis(4,4-dimethylpentyl)-N1,N2-dimethyl-
cyclohexane-1,2-diamine (R,R)-8
(1S,2S)-(ꢀ)-1,2-diaminocyclohexane
D-tartrate (1.41 g, 5.3 mmol)
in DCM (8 mL) and NaOH (1.0 g, 25.0 mmol) in water (6 mL) at
0 °C. The resulting mixture was stirred at room temperature for
24 h. The two layers were separated and the aqueous layer was
extracted with DCM (4 ꢁ 20 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure to give the bis-amide as a yellow solid. A solution
of the crude bis-amide (max. 5.3 mmol) in anhydrous THF (10 mL)
was added dropwise to a stirred suspension of LiAlH4 (0.60 g,
15.9 mmol) in anhydrous THF (10 mL) at 0 °C, under an N2 atmo-
sphere. The resulting mixture was heated at reflux for 24 h. The
reaction mixture was allowed to cool to 0 °C and Et2O (20 mL)
was carefully added. The reaction mixture was quenched by the
slow addition of water (1.0 mL, 1 vol. equiv wrt LiAlH4), 10% aq
NaOH solution (1.0 mL, 1 vol. equiv wrt LiAlH4), water (3.0 mL,
3 vol. equiv wrt to LiAlH4) and was allowed to stir for 1 h, an off-
white precipitate was observed. The mixture was filtered through
a pad of CeliteÒ to remove the inorganic salts and washed with
Et2O (2 ꢁ 30 mL). The filtrate was dried over MgSO4, filtered and
evaporated under reduced pressure to yield (S,S)-3 as a yellow oil
which was used in the next step without further purification
Prepared as described for (S,S)-8 from (R,R)-4 to yield (R,R)-8 as
a pale yellow oil (850 mg, 59%). [
a]
20 = ꢀ16.4 (c 0.5, CHCl3).
D
4.2.6. (1R,2R)-N1-(3,3-Dimethylbutyl)-N1,N2,N2-trimethylcyclo-
hexane-1,2-diamine (R,R)-9
(1R,2R)-(+)-1,2-Diaminocyclohexane L-tartrate (4 g, 15.2 mmol)
was dissolved in formic acid (6 mL, 90%, 159 mmol) and formalin
(8 mL, 37%, 97.6 mmol) was added slowly at room temperature.
The reaction mixture was allowed cool and basified until pH 14.
The aqueous layer was extracted with Et2O (3 ꢁ 20 mL). The
organic layers were combined and dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to afford the
crude product, which was purified by Kugelrohr distillation to give
(1R,2R)-N1,N1,N2,N2-tetramethylcyclohexane-1,2-diamine as
a
colourless oil (1.85 g, 71%).34
Next, t-BuLi (4.4 mL, 1.7 M in pentane, 7.5 mmol) was slowly
added to a stirred solution of (1R,2R)-N1,N1,N2,N2-tetramethylcy-
clohexane-1,2-diamine (850 mg, 5 mmol, in anhydrous pentane
(25 mL) at ꢀ78 °C. The reaction mixture was allowed warm to
room temperature and stirred for 6 h. The mixture was cooled to
ꢀ50 °C and 1-bromo-2,2-dimethylpropane (1.26 mL, 10 mmol)
was added slowly. The resulting solution was allowed warm to
room temperature overnight. Next, 2 M aq NaOH solution was
added until the reaction mixture was basic (pH 14). The mixture
was extracted with Et2O (5 ꢁ 20 mL). The organic layers were com-
bined, dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by column
chromatography (DCM with 5% MeOH and 1% NEt3) to yield (R,R)-9
(1.10 g, 74%).
a,
a0-Dibromo-o-xylene (486 mg, 1.84 mmol) was
added to a stirred solution of (S,S)-3 (1.84 mmol) in DCM (10 mL)
at room temperature. Two portions of LiOHꢂH2O (77 mg,
1.84 mmol) were added after 4 h and 8 h. The resulting solution
was stirred for 16 h at room temperature. Water (10 mL) was
added and the resulting layers separated. The aqueous layer was
washed with DCM (3 ꢁ 30 mL). The organic layers were combined,
dried over MgSO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by column chromatography
(3:1 hexane:Et2O) on silica gel to yield (S,S)-11 as a pale yellow
as a colourless oil (401 mg, 30%). [
(NaCl)
a
]
D
22 = ꢀ47.2 (c 0.26, CHCl3). IR
m
max: 2929–2774, 1450, 1363 cmꢀ1
.
1H NMR (300 MHz,
oil (555 mg, 78% yield). [
a] :
20 = +7.9 (c 1.0, CHCl3). IR (NaCl) mmax
D
CDCl3): d 0.83 (9H, s), 0.97–1.20 (4H, m), 1.24–1.40 (2H, m),
1.55–1.82 (4H, m), 2.14 (3H, s), 2.23 (6H, s), 2.28–2.50 (4H, m)
ppm. 13C NMR (75.5 MHz, CDCl3): d 23.9, 24.5, 25.9 (2C), 29.8
(3C), 30.0, 36.6, 40.5 (2C), 42.2, 50.4, 62.3, 63.8 ppm. HRMS (ESI)
m/z calcd for C15H33N2 [M+H]+: 241.2644, found 241.2644.
2951–2856, 1466, 1363 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.91
.
(18H, s), 0.97–1.08 (2H, m), 1.14–1.32 (2H, m), 1.31–1.76 (8H,
m), 2.47–2.77 (6H, m), 3.87, 4.29 (2H each one, 2 ꢁ d,
J = 13.1 Hz), 7.08–7.21 (4H) ppm. 13C NMR (75.5 MHz, CDCl3): d
26.2 (2C), 29.3 (2C), 29.7 (6C), 30.1 (2C), 43.0 (2C), 48.3 (2C),
56.6 (2C), 63.9 (2C), 126.9 (2C), 129.6 (2C), 139.6 (2C) ppm. HRMS
(ESI) m/z calcd for C26H45N2 [M+H]+: 385.3583, found 385.3587.
4.2.7. (1R,2R)-N1,N2-Dimethyl-N1,N2-bis(4-methylpentyl)cyclo-
hexane-1,2-diamine, (R,R)-10
Triethylamine
(3.85 mL,
28.6 mmol)
and
1-bromo-4-
4.3. General procedure for the asymmetric alkylation of
dimethylhydrazones
methylpentane (4.58 mL, 32.5 mmol) were added to a stirred solu-
tion of (R,R)-4 (1.85 g, 13 mmol) in toluene (19.5 mL). The resulting
mixture was stirred at reflux for 24 h. The resulting solution was
allowed cool to room temperature and acidified with 1 M aq HCl
solution to pH 1. The aqueous layer was separated and the organic
layer was washed with water (2 ꢁ 10 mL). The aqueous washes
were combined and basified with 10% NaOH solution to pH 14.
The resulting mixture was extracted with Et2O (3 ꢁ 50 mL). The
organic layers were combined, dried over MgSO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by Kugelrohr distillation to yield (R,R)-10 as a pale yellow oil
Anhydrous toluene (2 mL) and ligand (1.2 mmol) were added to
a Schlenk tube under an N2 atmosphere at room temperature. s-
BuLi (1.4 M, 1.1 mmol) was then added dropwise at ꢀ78 °C and
allowed to stir for 30 min. Dimethylhydrazone 12 or 13 (1 mmol)
was added dropwise at ꢀ78 °C, allowed to warm to room temper-
ature and stirred for 6 h. The reaction was cooled to ꢀ30 °C and
electrophile (1.2 mmol) was added slowly dropwise. This mixture
was allowed to stir at ꢀ30 °C for 22 h. At ꢀ30 °C, satd NH4Cl
(0.5 mL) was added and the mixture allowed warm to room tem-
perature. Et2O (30 mL) was added and the mixture washed with
NH4Cl (3 ꢁ 10 mL). The organic layer was dried over anhydrous
(3.20 g, 79%). [
a]
20 = ꢀ21.7 (c 1.0, CHCl3). IR (NaCl)
mmax: 2930–
D
2789, 1466, 1366 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 0.81 (12H,