192 JOURNAL OF CHEMICAL RESEARCH 2013
and the fraction of 118–126 °C was collected as a light yellow oil
(9.2 g, 83%). H NMR (δ, CDCl3): 2.23 (s, 3H), 1.75–1.71 (m, 2H),
followed by adjusting the pH from 2 to 10 to yield 7-methyl-7-
azabicyclo[4.1.0]-heptane 3, which was directly subjected to
the next reaction without purification. Ring-opening reactions
of compound 3 with a methylamine aqueous solution was
complete in a sealed reactor at 110 °C after 6h to yield
rac-trans-N1,N2-dimethylcyclohexane-1,2-diamine 4. Various
catalysts such as NH4Cl, BF3–Et2O were investigated. It was
shown that using NH4Cl as catalyst was the optimum to obtain
the desired compound 4. The ratio of reactants was also inves-
tigated and compound 3:methylamine = 1:2 was the optimum
under similar conditions.
1
1.70–1.66 (m, 2H), 1.36–1.34 (m, 2H), 1.23–1.18 (m, 2H), 1.16–1.05
(m, 2H). HRMS calcd for C7H14N (M+1) 112.1126, found 112.1141.
rac-trans-N1,N2-Dimethylcyclohexane-1,2-diamine (4): A mixture
of 7-methyl-7-azabicyclo[4.1.0]-heptane 3 (11.1 g, 0.1 mol) and 25%
aqueous methylamine (18.6 g, 0.15 mol) and NH4Cl (0.27 g, 0.005
mol) was added into the sealed reactor and stirred for 5 h at 110 °C.
The solution was cooled and evaporated to dryness under reduced
pressure to give the pale yellow oil: 12.4 g, yield 85%. The crude
product was used directly in the resolution without further purifica-
1
tion. (purity≥95% by GC). H NMR (δ, CDCl3): 2.35 (s, 6H), 2.08–
Finally, we investigated the resolution of rac-trans-N1,N2-
dimethylcyclohexane-1,2-diamine using tartaric acid (TA) and
dibenzyl tartaric acid (DBTA) and found that both are efficient
resolving agent. Considering the cost for large scale-up, the
cheaper TA was chosen as the resolving agent. Rac-trans-
N1,N2-dimethylcyclohexane-1,2-diamine was reacted with
0.5 equiv. (L)-TA in ethanol to yield diastereomeric salts of
(1S,2S)-4-(L)-TA following filtration. Then dichloromethane
was added and basification with potassium hydroxide gave
a single isomer of (1S,2S)-4 in 42% yield (98.3% ee). To the
filtrate in the above step was added 0.5 equiv. (D)-TA and
reflux for 1h, followed by filtration and basification with
potassium hydroxide gave the other isomer (1R,2R)-4 in 41%
yield (98.5% ee).
In conclusion, we have developed a practical method for the
preparation of enantiomerically pure trans-N1,N2-dimethylcy-
clohexane-1,2-diamine from an inexpensive starting material
through four simple steps. In the whole procedure, the product
of every step was used directly for the next step without purifi-
cation. The advantages of our procedure include mild reaction
conditions, easy work-up and good yields.
1.97 (m, 6H), 1.68–1.64 (m, 2H), 1.20–1.15 (m, 2H), 0.96–0.87 (m,
2H). IR (film) νmax 3300, 2930, 2852, 1550, 1438, 1150, 1098, 1040.
HRMS Calculated for C8H19N2 (M+1) 143.1458, found 143.1452.
(1S,2S)-N1,N2-Dimethylcyclohexane-1,2-diamine (1S,2S)-(4): (L)-
TA (45 g, 0.3 mol) was added to the solution of rac-trans- N1,N2-
dimethylcyclohexane-1,2-diamine 4 (85.2 g, 0.6 mol) in absolute
EtOH (300 mL) at room temperature and the mixture was heated to
reflux with agitation for 1 h. After cooling to room temperature, the
mixture was filtered and the collected solid was washed with absolute
EtOH. The filtrate was put aside for next step. The solid was sus-
pended in CH2Cl2 (180 mL) and 2 N KOH (300 mL) was added into
the mixture until pH=9–10. The mixture was stirred at room tempera-
ture to give a clear heterogeneous solution when stirring ceased. After
separation, the aqueous phase was extracted additionally two times
with the same amount of CH2Cl2 and the combined organic phases
were dried with Na2SO4, filtered, and then concentrated to afford
(1S,2S)-4 as a waxy solid upon standing: 35.7 g, yield 42% (98.3% ee
by HPLC). [α]D20 = +130.3 (c 1.6, CH2Cl2). 1H NMR (δ, CDCl3): 2.38
(s, 6H), 2.08–1.97 (m, 6H), 1.70–1.67 (m, 2H), 1.20–1.16 (m, 2H),
0.93–0.90 (m, 2H). HRMS calcd for C8H19N2 (M+1) 143.1458, found
143.1450.
(1R,2R)-N1,N2-Dimethylcyclohexane-1,2-diamine (1R,2R)-(4): (D)-
TA (45 g, 0.3 mol) was added to the filtrate in the above step and the
mixture was heated to reflux with agitation for 1h. The subsequent
work-up was performed as described above. (1R,2R)-4 was obtained
20
Experimental
as a waxy solid: 36.4 g, yield 43% (99.0% ee by HPLC). [α]D
=
–130.9 (c 1.6, CH2Cl2) [cf. lit.13 [α]D = –136.2 (c 1.9, CHCl3)]. H
NMR (δ, CDCl3): 2.39 (s, 6H), 2.09–1.97 (m, 6H), 1.69–1.64 (m,
2H), 1.20–1.15 (m, 2H), 0.96–0.89 (m, 2H). HRMS calcd for C8H19N2
(M+1) 143.1458, found 143.1462.
20
1
The starting material and other reagent were purchased from common
commercial suppliers and were used without further purification. IR
spectra were recorded on a Spectrum RX IR spectrophotometer. NMR
spectra were recorded on a Bruker Avance DMX 400 MHz spectro-
meter using CDCl3 as solvent, and TMS as the internal standard. High
resolution mass spectra were recorded on an Applied Biosystems
Mariner System 5303. Enantiomeric excess (ee) determinations were
carried out using HPLC with a Chiralcel AD-H column on an Agilent
1200 Series.
Received 24 December 2012; accepted 20 January 2013
Paper 1201694 doi: 10.3184/174751913X13626731204890
Published online: 19 April 2013
trans-2-(Methylamino)cyclohexanol (2): Cyclohexene oxide
1
(29.4 g, 0.3 mol) was added into 25% aqueous methylamine (55.8 g,
0.45 mol) with stirring in an ice bath, and the resulting mixture was set
up in a sealed reactor, which was maintained at 80 °C for 5h. Then, it
was cooled to room temperature and excess aqueous methylamine
was removed under in vacuo. Toluene (300 mL) was added to the
residue and evaporated to remove the residual water. The residue was
dried in vacuo to afford a light yellow oil (38.6 g, 97%). 1H NMR (δ,
CDCl3): 3.27–3.18 (m, 3H), 2.40 (s, 3H), 2.15 (m, 1H), 2.07 (s, 1H),
2.01–1.92 (m, 1H), 1.74–1.69 (m, 2H), 1.33–1.16 (m, 3H), 1.01–0.92
(m, 1H). HRMS cald for C7H16NO (M+1) 130.1232, found 130.1219.
7-Methyl-7-azabicyclo[4.1.0]-heptane (3): The solution of DEAD
(22 mL, 0.12 mol) in CH2Cl2 (80 mL) was added dropwise into a solu-
tion of PPh3 (31.44 g, 0.12 mol) and trans-2-(methylamino)cyclohexa
nol 2 (13 g, 0.1 mol) in CH2Cl2 (180 mL) in an ice bath. The reaction
mixture was stirred at room temperature for 6h. 2N HCl (100 mL) was
added and the resulting mixture was added to a separating funnel.
After separation, the aqueous solution was neutralised using 2N KOH
until pH=9–10 and extracted with CH2Cl2 (200 mL×2). The combined
organic layer was washed with brine, dried over anhydrous Na2SO4
and filtered. The solvents were removed under reduced pressure to
afford the crude product 3, which was distilled at atmospheric pressure
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