was added to a suspension of NaH (65%) (75 mg, 2 mmol,
prewashed with hexane) in THF at 60 ЊC with stirring under
nitrogen atmosphere. After 0.5 h EtI (0.16 ml, 2 mmol) was
added. After 2 h the flask was cooled in an ice bath and 10 ml of
brine were added slowly. The organic phase was separated and
the aqueous phase extracted with ethyl acetate. The combined
organic phase was dried over MgSO4 and the solvent evapor-
ated under reduced pressure. δH (CDCl3) 1.16 and 1.18 (t, J 7.0,
3 H total), 1.61 (m, 4 H), 1.75 (m, 2 H), 1.99 (m, 2 H), 3.25 (m, 1
H), 3.29 and 3.31 (s, 3 H total), 3.45 and 3.46 (quart, J 7.0, 2 H
total). Compound 1 was also prepared from 4-ethoxycyclo-
hexanol 27 (R = Et) (72 mg, 0.5 mmol) by the procedure
described above, using MeI (0.12 ml, 2 mmol) instead of EtI.
The 1c:1t concentration ratio was 1.2:1 (GC–MS).
1 h water (1 ml), 3 NaOH (0.5 ml) and 30% H2O2 (2 ml) were
added slowly in an ice bath. The mixture was extracted with
ethyl acetate, the organic phase was washed several times with
water, dried over MgSO4 and the solvent evaporated under
reduced pressure to give a mixture of deuteriated 4- and 3-
methoxycyclohexanol in diglyme,32 which were identified by
GC–MS (standard 3-methoxycyclohexanol for comparison was
prepared independently).33 [2H1] > 98%, [2H0] < 2%. The 3-:4-
methoxycyclohexanol isomers concentration ratio was 3:2,
based on a GC–MS analysis of the diethers. cis-[2-2H1]-4-
Ethoxycyclohexanol 32 (R = Et) was prepared by the procedure
described above for 32 (R = Me), starting from 31 (R = Et).
[2H1] > 98%, [2H0] < 2%.
cis-[2-2H1]-1-Methoxy-4-ethoxycyclohexane 7. Etherification
of 32 (R = Et) with MeI to 7 was carried out by the procedure
described above for the preparation of 1 from 27. 7 was ob-
tained as a mixture of deuteriated 1,4- and 1,3-dialkoxycyclo-
hexane in diglyme, which was used for the GC–MS analyses
without further purification (standard 1-ethoxy-3-methoxy-
cyclohexane for comparison was prepared independently).33
[2H1] > 98%, [2H0] < 2%. The 7c:7t concentration ratio was 1:2
(GC–MS).
4-Methoxy- and 4-ethoxy[2,2,6,6-2H4]-cyclohexanone 28 (R ؍
Me) and 28 (R ؍
Et). A suspension of 26 (R = Me) (2.6 g, 20
mmol) in D2O (10 ml) and Et3N (0.2 ml) was stirred overnight
at room temp. The reaction mixture was extracted with ethyl
acetate, the organic phase was dried over MgSO4 and the sol-
vent evaporated under reduced pressure.31 [2H4] > 97%, [2H3]
< 3%. 28 (R = Et) was prepared by a similar route starting with
26 (Et). [2H4] > 97%, [2H3] < 3%.
1-Ethoxy-4-methoxy[2H4]-cyclohexanes 3 and 4. These iso-
topomers were prepared from 28 (R = Me) and 28 (R = Et) by
the procedure described above for the preparation of 1 from 26.
[2H4 > 95%, [2H3] < 5%.
cis-[2-2H1]-1-Ethoxy-4-methoxycyclohexane 8. This com-
pound was prepared from 32 (R = Me) by the procedure
described above for 7, but using EtI instead of MeI.
[2H1] > 98%, [2H1] < 2%. The 8c:8t concentration ratio was
1.4:1 (GC–MS).
[1-2H1]- and [4-2H1]-1-Ethoxy-4-methoxycyclohexane 5 and 6.
LiAlD4(33 mg, 0.78 mmol) was added to the mixture of 4-
methoxycyclohexanone 26 (R = Me) (50 mg, 0.39 mmol) in
ether in water–ice bath with stirring under nitrogen atmosphere.
After 15 min the bath was removed and stirring continued at
room temp. for 1 h. More diethyl ether was added followed by
several drops of water while stirring until the solid became
white. The suspension was dried with MgSO4, filtered, and the
solvent evaporated under reduced pressure to afford 1-[2H1]-4-
methoxycyclohexanol 30 (R = Me) (95%). 30 (R = Et) was pre-
pared from 26 (R = Et) by an analogous procedure. 5 and 6
were prepared from 30 (R = Me) and 30 (R = Et) respectively by
the procedure described above for the preparation of 1 from 26.
[2H4] > 95%, [2H3] < 5%. The concentration ratio was 2.5:1,
and that of 6c:6t was 2.9:1 (GC–MS).
Acknowledgements
We thank Professor H. Schwarz (TU, Berlin) for helpful discus-
sions. This work was supported by the Fund for Promotion
of Research at the Technion. T. M. thanks the Minerva
Foundation for a Postdoctoral Fellowship and the Fond der
Chemischen Industrie for a Liebig Scholarship. We are grateful
to Mr A. Etinger for assistance in mass spectral measurements.
We would like to acknowledge the German Federal Ministry of
Science, Research, Technology and Education (BMBF) and the
Minerva Foundation for their generous support.
4-Methoxycyclohexene 31 (R ؍
Me). A solution of toluene-p-
sulfonyl chloride (2.52 g, 13.23 mmol) in CHCl3 (50 ml) was
added slowly to a solution of 4-methoxycyclohexanol 27
(R = Me) (1.72 g, 13.23 mmol) in pyridine (15 ml) at 0 ЊC. After
stirring overnight at 0 ЊC, the solution was washed with water,
5% HCl, saturated NaHCO3 and brine. The organic phase was
dried over MgSO4 and the solvent evaporated under reduced
pressure affording 94% of 4-methoxycyclohexyl tosylate.
δH (CDCl3) d: 1.66 (m, 4 H), 1.85 (m, 4 H), 2.42 (s, 3 H), 3.21 (m,
1 H), 3.27 (s, 3 H), 4.57 (m, 1 H), 7.30 (d, J 8, 2 H), 7.77 (d, J 8,
2 H). The foregoing tosylate (3.55 g, 12.5 mmol) and 75 ml of
12% KOH were placed in a distillation apparatus at 110 ЊC.
More 12% KOH was added during the distillation. The distil-
late (collected for 7–8 h of heating) was extracted with diethyl
ether, the organic phase was dried over MgSO4 and the solvent
evaporated under reduced pressure in a cold bath affording 35%
of 31 (R = Me). δH (CDCl3) 1.9–2.1 (m, 5 H), 2.35 (dd, 1 H),
3.33 (s, 3 H), 3.44 (m, 1 H), 5.61 (m, 2 H).
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4-Ethoxycyclohexene 31 (R ؍
Et). This compound was pre-
pared by the procedure described above for 31 (R = Me), but
using 28 (R = Et) (3.52 g, 11.8 mmol) and heating at 130 ЊC
(60%). δH (CDCl3) 1.19 (t, J 7, 3 H), 1.91–2.1 (m, 5 H), 2.36 (m, 1
H), 3.52 (quart, J 7, 2 H), 5.59 (m, 2 H).
cis-2-[2-2H1]-4-Methoxycyclohexanol 32 (R ؍
Me). A solu-
tion of 4-methoxycyclohexene 31 (Me) (0.14 g, 1.25 mmol) in 5
ml of diglyme was added to NaBD4 (0.03 g, 0.71 mmol) in
diglyme (2 ml) at room temp. A solution of BF3–Et2O (0.2 ml,
1.57 mmol) in diglyme (3 ml) was added slowly (foaming occurs
during the addition). After stirring at room temp. for another
13 F. W. McLafferty and F. Turecek, Interpretation of Mass Spectra,
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J. Chem. Soc., Perkin Trans. 2, 1997
1233