Baeyer-Villiger Oxidations of Substituted Cyclohexanones
J . Org. Chem., Vol. 66, No. 3, 2001 737
(4.8 mmol, 0.74 g), CH2I2 (24.0 mmol, 6.43 g, 1.93 mL), and
Et2O (45 mL). A zinc-copper couple prepared according to
Shank and Schechter35 (30 mmol, 1.96 g) was added, and the
mixture was held at reflux for 12 h. After this time, additional
portions of CH2I2 (24.0 mmol, 6.43 g, 1.93 mL) and zinc-copper
couple (30 mmol, 1.96 g) were added and the reaction was
continued at reflux for an additional 17 h. After this time, the
reaction mixture was cooled to room temperature, solids were
removed by filtration, and the filtrate was washed with 60 mL
of Et2O. The combined organics were placed in a 500 mL
round-bottom flask along with 100 mL of 1 M HCl. The
mixture was stirred vigorously at room temperature for 1 h;
then the layers were separated and the aqueous fraction was
extracted with Et2O (4 × 100 mL). The combined organics were
dried with MgSO4 and concentrated by rotary evaporator; then
the crude product was purified by silica gel chromatography
to afford 0.29 g (48% yield) of the title compound as a light
yellow oil whose spectral data were identical to those reported
previously by Rickborn.21
shaken at 150-200 rpm at 37 °C until they reached an O.D.600
between 0.3 and 0.4; then IPTG was added to a final concen-
tration of 0.10 mM. If cyclodextrins were required, they were
added at this time. The cultures were shaken at 150 rpm at
room temperature for 30 min; then the ketone was added neat
and the cultures were shaken at room temperature at 150 rpm.
Samples for GC analysis were prepared by mixing 100 µL of
the reaction mixture with 100 µL of EtOAc and then vortexing
vigorously for ca. 30 s. A 1 µL portion of the organic extract
was analyzed by GC. When >95% of the starting ketone had
been consumed, the reaction mixture was centrifuged at 5000
× g for 10 min at 4 °C. The pellet was extracted with 20 mL
of EtOAc. The supernatant was saturated with NaCl and
extracted with EtOAc (4 × 60 mL); then the combined organic
extracts were dried with MgSO4 and concentrated by rotary
evaporator. The lactone was purified by flash chromatography
on silica gel.
(S)-5-Meth yl-2-oxep a n on e 2a . Using the general proce-
dure outlined above, 1.0 mmol (113 mg) of ketone 1a was
oxidized in a 100 mL culture over 28.5 h to afford lactone 2a
(78 mg, 61% yield). Spectral data agreed with those reported
previously.13
5,5-Dim eth yl-2-oxep a n on e 2b. Using the general proce-
dure outlined above, 1.0 mmol (126 mg) of ketone 1b was
oxidized in a 100 mL culture over 28 h to lactone 2b (86 mg,
61% yield). Spectral data agreed with those reported previ-
ously.38
4-Eth yl-4-h yd r oxycycloh exa n on e 1h . Magnesium metal
(55 mmol, 1.3 g) and 25 mL of anhydrous Et2O were placed in
a 150 mL flask equipped with a dropping funnel and reflux
condenser. Ethyl bromide (45 mmol, 4.9 g, 3.8 mL) dissolved
in 25 mL of anhydrous Et2O was added at a rate sufficient to
maintain a gentle reflux; this was continued for an additional
hour at room temperature. Ketal 3 (7.5 mmol, 1.2 g) dissolved
in 20 mL of anhydrous Et2O was added dropwise; then stirring
was continued for an additional 1.5 h at room temperature.
The reaction was quenched by adding 50 mL of water. The
organic layer was separated, and the aqueous phase was
extracted with Et2O (3 × 150 mL). The combined organics were
dried with MgSO4, and the solvent was removed by rotary
evaporator. The crude product was dissolved in 100 mL of
aqueous HCl (pH ∼ 3) and stirred at room temperature for 4
h. After being extracted with EtOAc (3 × 180 mL), the
combined organics were dried with MgSO4 and the solvent was
removed by rotary evaporation. The crude product was purified
by chromatography on silica gel using 2:3 EtOAc:petroleum
ether to afford the title compound as colorless crystals (0.76
(S)-5-Eth yl-2-oxep a n on e 2c. Using the general procedure
outlined above, 1.0 mmol (126 mg) of ketone 1c was divided
into equal portions and oxidized in two 100 mL cultures over
6 h in the presence of 1.0 equiv (1.14 g) of â-cyclodextrin to
afford lactone 2c (129 mg, 91% yield). Spectral data agreed
with those reported previously.13
5-Eth yl-5-m eth yl-2-oxep a n on e 2d . Using the general
procedure outlined above, 1.0 mmol (140 mg) of ketone 1d was
divided into equal portions and oxidized in two 100 mL
cultures over 27 h in the presence of 1.0 equiv (1.14 g) of
â-cyclodextrin to afford lactone 2d (142 mg, 91% yield). IR
1
(neat) v 1737 cm-1. H NMR δ 4.15-4.28 (2H, m), 2.53-2.69
1
g, 70% yield): mp 48-49 °C. IR (neat) v 3429, 1710 cm-1. H
(2H, m), 1.48-1.74 (4H, m), 1.30-1.43 (2H, m), 0.96 (3H, s),
0.85 (3H, t, J ) 7.6 Hz) ppm. 13C NMR δ 176.3, 103.3, 64.5,
39.8, 34.2, 33.4, 29.6, 24.1, 7.7 ppm. MS: m/e 156 (M+, 1.5%),
111, (75%), 97 (76%), 69 (100%), 55 (89%).
NMR δ 2.80 (2H, ddd, J ) 13.9, 13.7, 6.4 Hz), 2.25 (2H, dm, J
) 14.5 Hz), 1.98 (2H, dm, J ) 13.0 Hz), 1.79 (2H, ddd, J )
13.4, 13.3, 4.9 Hz), 1.66 (2H, q, J ) 9.5 Hz), 0.98 (3H, t, J )
9.5 Hz) ppm. 13C NMR δ 212.5, 70.3, 37.0, 36.3, 35.0, 7.7 ppm.
4-Br om ocycloh exa n on e 1j. Lithium bromide (112 mmol,
10 g) was dissolved in 50 mL of acetone in a flask equipped
with a reflux condenser; then 4-tosyloxycyclohexanone (15
mmol, 4.0 g) was added and the mixture held at reflux until
TLC showed complete consumption of the starting material.
The solvent was removed by rotary evaporator, and the residue
was dissolved in a minimum amount of water and extracted
with EtOAc (3 × 50 mL). The combined organics were washed
with 0.1 M KOH and brine, dried with MgSO4, and concen-
trated by rotary evaporation. Silica gel chromatography using
1:3 Et2O:petroleum ether followed by CH2Cl2 afforded the title
compound as a colorless oil (1.58 g, 59% yield) whose spectral
data agreed with literature values.36
5,5-Dieth yl-2-oxep a n on e 2e. Using the general procedure
outlined above, 1.0 mmol (154 mg) of ketone 1e was divided
into equal portions and oxidized in two 100 mL cultures over
28.5 h in the presence of 1.0 equiv (1.14 g) of â-cyclodextrin to
afford lactone 2e (101 mg, 60% yield). IR (neat) v 1735 cm-1
.
1H NMR δ 4.19-4.23 (2H, m), 2.57-2.61 (2H, m), 1.64-1.67
(2H, m), 1.54-1.58 (2H, m), 1.30-1.43 (4H, m), 0.80 (6H, t, J
) 7.6 Hz) ppm. 13C NMR δ 176.4, 64.2, 37.7, 36.2, 31.1, 29.2,
28.3, 7.3 ppm. MS: m/e 170 (M+, 0.7%), 141 (50%), 69 (41%),
55 (100%).
6-Oxa sp ir o[2.6]n on a n -7-on e 2f. Using the general pro-
cedure outlined above, 1.0 mmol of ketone 1e was oxidized in
a 100 mL culture to lactone 2f (103 mg, 74% yield). IR (neat)
1
v 1728 cm-1. H NMR δ 4.30 (2H, m), 2.73 (2H, m), 1.66 (2H,
m), 1.56 (2H, m), 0.43 (4H, br d, J ) 1.4 Hz) ppm. 13C NMR δ
176.0, 68.4, 38.7, 33.7, 32.5, 21.5, 12.8 ppm. MS: m/e 140 (M+,
1.4%), 83 (51%), 67 (100%), 54 (42%).
4-Iodocycloh exan on e 1k. The general procedure for prepa-
ration of 1j was followed. Lithium iodide (50 mmol, 7.0 g) was
reacted with 4-tosyloxycyclohexanone (10 mmol, 2.7 g) to afford
the title compound as white crystals (1.1 g, 47% yield): mp
43-43.5 °C, lit. mp 62 °C.37 Spectral data agreed with
literature values.37
Gen er a l P r oced u r e for Ba eyer -Villiger Oxid a tion s by
Wh ole Cells of E. coli BL21(DE3)(p MM4). A 1 mL aliquot
from an overnight culture of BL21(DE3)(pMM4) (optical
density at 600 nm [O.D.600] of 4 to 5) was added to one or two
100 mL portion of LB medium supplemented with 200 µg/mL
of ampicillin in a 500 mL Erlenmeyer flask. The cultures were
4,6-Dih yd r oxyh exa n oic a cid , γ-La cton e 2g. Using the
general procedure outlined above, 0.88 mmol (100 mg) of
ketone 1g was oxidized in a 100 mL culture to afford lactone
2g (73 mg, 64% yield). Spectral data agreed with those
reported previously.39
5-Eth yl-5-h yd r oxy-2-oxep a n on e 2h . Using the general
procedure outlined above, 0.35 mmol (50 mg) of ketone 1h was
oxidized in the presence of 0.44 mmol (0.5 g) of â-cyclodextrin
in a 100 mL culture to afford lactone 2h (30 mg, 54% yield).
IR (neat) v 3435, 1764 cm-1. 1H NMR δ 3.80 (2H, m), 2.61 (2H,
(35) Shank, R. S.; Schechter, H. J . Org. Chem. 1959, 24, 1825-1826.
(36) Engel, P. S.; Kitamura, A.; Keys, D. E. J . Org. Chem. 1987, 52,
(38) Heslinga, L.; van der Linde, R.; Pabon, H. J . J .; van Dorp, D.
A. Recl. Trav. Chim. Pays-Bas 1975, 94, 262-273.
(39) Taschner, M. J .; Black, D. J . J . Am. Chem. Soc. 1988, 110,
6892-6893.
5015-5021.
(37) Curran, D. P.; Chang, C.-T. J . Org. Chem. 1989, 54, 3140-
3157.