Design and Synthesis of Chiral N-Chloroimidodicarbonates
SCHEME 2. Asymmetric Chlorination of 8d using Chiral Non-C2-Symmetric Chlorinating Agents 11
a Isolated yields after column chromatography.
SCHEME 3. Proposed TS
was used directly for the next step without further purification.
25
[R]D -74.43 (c 1.0, CH2Cl2); IR (KBr, cm-1): 690, 833, 945,
1145, 1170, 1458, 1776 (CO), 2959; 1H NMR (400 MHz, CDCl3):
δ 0.80 (d, J ) 7.0 Hz, 3H), 0.92 (d, J ) 7.0 Hz, 3H), 0.93 (d, J )
6.5 Hz, 3H), 0.85-1.30 (m, 3H), 1.30-1.60 (m, 2H), 1.60-1.80
(m, 2H), 1.80-2.05 (m, 1H), 2.05-2.25 (m, 1H), 4.73 (dt, J )
4.5, 11.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 16.2, 20.5,
21.8, 23.3, 26.2, 31.4, 33.7, 40.1, 46.8, 83.9, 149.9.
(1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexylcarbamate (6a). A
solution of chloroformate 5a (1.5 g, 6.86 mmol) in THF (15 mL)
was cooled in an ice bath. 50% aqueous ammonia solution (15 mL)
was dropwise added with vigorous stirring. The reaction mixture
was stirred at rt overnight to remove the excess ammonia. The
organic layer was separated, and the aqueous layer was extracted
with ethyl acetate (2 × 20 mL). Combined organic layers were
washed with water (15 mL) and brine (15 mL), dried over
anhydrous Na2SO4, and evaporated to afford the title carbamate in
quantitative yield (1.34 g), which may be directly used for the next
step without any purification. Recrystallization from ethanol/water
groups plays an important role in the enantioselectivity of the
reaction. Asymmetric induction was also observed for non-C2-
symmetric chiral chlorinating agents such as (1R,2S,5R)-(-)-
menthyl-N-chloroimidodicarbonate and (1R,2S,5R)-(-)-menthyl-
N-acetyl-N-chlorocarbamate. Further application of this chemistry
is underway in our laboratory.
25
gave pure 6a as a white solid. mp 155-157 °C; [R]D -75.16 (c
Experimental Procedures
1.0, CH2C12); IR (KBr, cm-1): 569, 787, 1049, 1340, 1408, 1612,
1684(CO), 2952, 3261, 3442; 1H NMR (200 MHz, CDCl3): δ 0.79
(d, J ) 6.9 Hz, 3H), 0.89 (d, J ) 6.5 Hz, 6H), 0.85-1.14 (m, 3H),
1.15-1.52 (m, 2H), 1.60-1.70 (m, 2H), 1.85-2.10 (m, 2H), 4.53
(dt, J ) 4.3, 10.8 Hz, 1H), 4.61 (br s, 2H); 13C NMR (50 MHz,
CDCl3): δ 16.4, 20.7, 22.0, 23.5, 26.2, 31.3, 34.3, 41.3, 47.3, 74.9,
157.1; Anal. Calcd for C11H21NO2: C, 66.29; H, 10.62; N, 7.03.
Found: C, 66.10; H, 10.75; N, 6.95.
All reactions were conducted with oven-dried glassware under
an atmosphere of argon (Ar). Commercial grade reagents were used
without further purification. Solvents were dried and distilled
following usual protocols. Flash chromatography was carried out
using silica gel (230-400 mesh). TLC was performed on aluminum-
backed plates coated with silica gel 60 with a F254 indicator.
1H NMR spectra were measured at 200 and 400 MHz and 13C
NMR spectra were measured at 50 and 100 MHz using CDCl3 and
C6D6 as solvents. 1H NMR chemical shifts were expressed in parts
per million (δ) downfield to CHCl3 (δ ) 7.26); 13C NMR chemical
shifts were expressed in parts per million (δ) relative to the central
CDCl3 resonance (δ ) 77.0) and C6D6 resonance (δ ) 128.0).
(1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexylimidodicarbon-
ate or (1R,2S,5R)-(-)-Menthyl-imidodicarbonate (1a). To a
stirred suspension of NaH (0.12 g, 60% in oil, 3.01 mmol) in dry
THF (15 mL) under argon was dropwise added a solution of
carbamte 6a (0.50 g, 2.51 mmol) in dry THF (15 mL) at 0 °C. The
reaction mixture was allowed to come to room temperature (25
°C) and was stirred for 2 h. The reaction mixture was again cooled
at 0 °C. Then, a solution of chloroformate 5a (0.60 g, 2.76 mmol)
in dry THF (15 mL) was added rapidly at 0 °C and immediately
quenched with an aqueous saturated NH4Cl solution (15 mL). The
reaction mixture was extracted with diethyl ether (4 × 15 mL).
The combined organic layers were washed with brine (30 mL),
dried over anhydrous Na2SO4, and concentrated to give the crude
1a. Flash chromatography over a silica gel column (diethyl ether/
petroleum ether ) 10:90) yielded 0.58 g (60%) as a white solid.
1
Coupling constants in H NMR were expressed in hertz.
(1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexane-1-chlorofor-
mate or (1R,2S,5R)-(-)-Menthyl-chloroformate (5a).4 A suspen-
sion of triphosgene (2.34 g, 7.88 mmol) in pyridine (1.80 mL, 22.11
mmol) and carbon tetrachloride (90 mL) was added to a stirred
solution of (1S,2S,3S,5R)-(-)-menthol 4a (3.0 g, 19.23 mmol) in
carbon tetrachloride (90 mL). The resulting solution was stirred at
55-60 °C for 6 h. The reaction mixture was cooled to ambient
temperature, and dichloromethane (150 mL) was added. The
solution was washed with water (2 × 75 mL) and brine (50 mL),
dried over anhydrous Na2SO4, and evaporated to afford the title
compound as a colorless oil in quantitative yield (4.15 g). This
33
mp 64-70 °C; [R]D -89.02 (c 0.4, CH2Cl2); IR (KBr, cm-1):
1
1093, 1176, 1495, 1713 (CO), 1795 (CO), 2957; H NMR (200
J. Org. Chem, Vol. 72, No. 13, 2007 4875