9184 J . Org. Chem., Vol. 62, No. 26, 1997
J ung et al.
and then 6-methyl-5-hepten-2-one (12) (130 mg, 1.03 mmol)
and benzyl chloromethyl ether (160 mg, 1.02 mmol). The
solution was stirred for 1 h and the dark green color gradually
faded to give a light yellow sediment. At this time 5 mL of
0.1 N HCl was added and the solution stirred for 10 min which
allowed the solids to dissolve and gave a slightly cloudy pale
yellow solution. The organic layer was separated, and the
aqueous phase was extracted with 5 × 10 mL of ether. The
organic phases were combined and washed with 5 mL each of
water and of saturated NaCl and then dried over K2CO3. After
the drying agent was removed by filtration, the solution was
evaporated and the crude product was vacuum distilled in a
Kugelrohr at 200 °C (1 mmHg) to give 242 mg of 6-methyl-1-
(phenylmethoxy)-5-hepten-2-ol as a colorless oil, which was
shown by 1H NMR to be 92.9% pure, implying a yield of
87.9%: 1H NMR (200 MHz, CDCl3) δ 7.40-7.25 (m, 5H), 5.12
(br t, J ) 7.1 Hz, 1H), 4.67 (s, 2H), 3.35 (d, J ) 9 Hz, 1 H),
3.30 (d, J ) 9 Hz, 1H), 2.32 (br s, 1H), 2.04 (q, J ) 7.8 Hz,
2H), 1.69 (s, 3H), 1.61 (s, 3H), 1.58 (m, 2H), 1.19 (s, 3H); 13C
NMR (50 MHz) δ 138.3, 131.5, 128.4, 127.6, 127.0, 125.0, 77.8,
73.5, 72.2, 39.0, 25.7, 23.7, 22.5, 17.6.
) 7.0 Hz, 1H), 2.2-1.5 (m, 6H), 1.59 (s, 3H), 1.52 (s, 3H), 0.85
(t, J ) 7.4 Hz, 3H); 13C NMR (50 MHz) δ 180.9, 132.0, 122.7,
77.4, 38.0, 31.7, 24.9, 21.8, 17.0, 7.1.
In a 25 mL oven-dried round-bottom flask with a reflux
condenser and drying tube was placed 2 mL of 1 M lithium
aluminum hydride (LAH, 2.0 mmol) in ether. Then sodium
2-ethyl-2-hydroxy-6-methyl-5-heptenoate (223 mg, 1.07 mmol)
in 6 mL of ether was added dropwise with stirring which
produced slight gas evolution. The solution was stirred for
15 min, and 5 mL of water was cautiously added to decompose
the excess LAH. Then 5 mL of 10% H2SO4 was added slowly
to clarify the solution. The organic phase was separated, and
the aqueous phase was extracted with 3 × 5 mL of ether. The
organic phases were combined and washed with 5 mL of water.
The solution was then dried over Na2SO4 and filtered, the
solution was evaporated, and the crude product was purified
by column chromatography on silica gel with a gradient
hexanes to 1:5 ethyl acetate/hexanes elution to give 179 mg
of the diol 10 as a colorless oil (97.1% yield): 1H NMR (200
MHz, CDCl3) δ 5.10 (br t, J ) 6.4 Hz, 1H), 3.46 (s, 2 H), 2.03
(br s, 2H), 1.98 (m, 2H), 1.68 (s, 3H), 1.62 (s, 3H), 1.52 (m,
4H), 0.88 (t, J ) 7.5 Hz, 3H); 13C NMR δ 132.0, 124.2, 74.9,
67.6, 35.2, 28.4, 25.7, 22.0, 17.6, 7.8.
A 100 mL oven-dried flask with a septum-capped sidearm
inlet was placed under a dry ice condenser connected to a
drying tube. Dry THF (2.5 mL) was added under argon, and
then 3.8 g of lithium wire cut into short pieces was added.
The dry ice condenser was chilled to -60 °C, and gaseous
ammonia was introduced by needle slowly through the septum
on the side inlet, which gave a dark blue solution with stirring
as the ammonia condensed. Enough ammonia was added to
increase the volume of the solution to 5 mL. Then 6-methyl-
1-(phenylmethoxy)-5-hepten-2-ol (150 mg, 0.60 mmol) in 2.5
mL of THF was added dropwise over 10 min. The solution
was stirred for an additional 2 min, the dry ice condenser was
removed, and 1.5 g of solid ammonium chloride was added with
gentle stirring. The mixture was allowed to warm to room
temperature very gradually to minimize foaming as the
ammonia evaporated. Saturated NaCl and ether (20 mL each)
were added, and the organic layer was separated. The aqueous
phase was extracted with 4 × 10 mL of ether, and the
combined organic phases were dried over K2CO3. After the
drying agent was removed by filtration, Kugelrohr vacuum
distillation at 150 °C (1 mmHg) gave 79 mg of the diol 9, as a
pure colorless oil (83.2% yield): 1H NMR (200 MHz, CDCl3) δ
5.05 (br t, J ) 7.0 Hz, 1H), 3.38 (d, J ) 10.9 Hz, 1H), 3.34 (d,
J ) 10.9 Hz, 1H), 2.29 (br s, 2H), 1.99 (app q, J ) 7.7 Hz, 2H),
1.62 (s, 3H), 1.55 (s, 3H), 1.45 (m, 2H), 1.11 (s, 3H); 13C NMR
(50 MHz) δ 132.0, 124.2, 73.0, 69.8, 38.5, 25.7, 23.2, 22.4, 17.6.
2-Eth yl-6-m eth yl-5-h ep ten e-1,2-d iol (10). A Grignard
reagent was made in the usual manner from 5-bromo-2-
methyl-2-pentene (13)9 (1.47 g., 9.0 mmol) and Mg turnings
(219 mg, 9.0 mmol) in 10 mL of dry THF. In another 50 mL
oven-dried round-bottom flask with a stir bar was added
sodium R-ketobutyrate (14) (744 mg, 6 0.0 mmol) and 10 mL
of dry ether under a dry ice condenser with a drying tube. This
flask was heated to 50 °C (reflux) in an oil bath, and the
Grignard solution was added via a large bore needle over 5
min with stirring.13 The solution was refluxed for 2 h and then
chilled in an ice bath while 10 mL of 2 N HCl was carefully
added with vigorous stirring. Over the next 15 min, the solids
gradually dissolved. The organic phase was separated, the
aqueous phase was extracted with 3 × 10 mL of ether, and
the combined organic phases were dried over MgSO4. The
solution was filtered and evaporated, and the crude product
was purified by column chromatography on silica gel with a
gradient hexane to 1:5 ethyl acetate/hexane elution to give 411
mg of sodium 2-ethyl-2-hydroxy-6-methyl-5-heptenoate, as a
colorless liquid which crystallized under refrigeration (32.9%
yield). Higher yields can be obtained by using a slightly larger
excess of the Grignard reagent.13 The melting point of the
product was determined to be 37-39 °C; however the product
appeared to be somewhat hygroscopic and attempts at further
drying with mild heat and high vacuum resulted in decompo-
sition at about 70 °C: 1H NMR (200 MHz, CDCl3) δ 5.02 (t, J
(E)-2-Meth yl-6-p h en yl-5-h exen e-1,2-d iol (11). A Grig-
nard reagent was made in the usual manner from 4-bromo-
1-phenyl-1-butene (15) (1.71 g, 8.1 mmol) and Mg turnings (364
mg, 15.0 mmol) in 15 mL of dry THF. Then 1-[(tetrahydro-
furan-2-yl)oxy]acetone (16) (1.3 g., 9.0 mmol) in 3 mL of dry
THF was added dropwise with stirring. Stirring was contin-
ued in a 50 °C oil bath for 30 min. Then the flask was
transferred to an ice bath and 8 mL of 2 N HCl was added
carefully, followed by stirring at room temperature for 30 min.
The organic phase was separated, and the aqueous phase was
extracted with 2 × 5 mL of ether. The combined organic
phases were washed with 4 mL of cold water and then dried
over Na2SO4. The drying agent was removed by filtration, and
the solution was evaporated down to a couple of milliliters.
At this time 10 mL of 3:1:1 acetic acid/water/THF was added,
and the solution was stirred overnight. The next day the
solution was poured carefully into 40 mL each of ether and of
saturated Na2CO3 which resulted in considerable bubbling.
Additional saturated Na2CO3 was added to bring the pH of
the solution to 7. The organic phase was separated, and the
organic phase was extracted with 2 × 25 mL of ether. The
combined organic phases were washed with 25 mL of saturated
NaCl and dried over MgSO4. The crude product in solution
was filtered, evaporated, and purified by column chromatog-
raphy on silica gel, eluting with hexanes to a 1:3 ethyl acetate/
hexane gradient to give 925 mg of the diol as a colorless oil
(55.4% yield) which began to crystallize into small white
nodules at room temperature; the process was completed in
the refrigerator overnight. The melting point of the product
was determined to be 65-66 °C: 1H NMR (200 MHz, CDCl3)
δ 7.35-7.07 (m, 5H), 6.35 (d, J ) 15.8 Hz, 1H), 6.15 (dt, J )
15.8, 6.3 Hz, 1H), 3.42 (d, J ) 11.0 Hz, 1H), 3.38 (d, J ) 11.0
Hz, 1H), 2.24 (m, 2H), 2.17 (br s, 2H), 1.58 (m, 2H), 1.14 (s,
3H); 13C NMR (50 MHz) δ 137.6, 130.5, 130.1, 128.5, 127.0,
125.9, 72.9, 69.8, 38.1, 27.4, 23.3.
5-Br om o-2-m eth yl-2-p en ten e (13).9 A Grignard reagent
was made in the usual manner from Mg turnings (2.43 g, 100
mmol), methyl iodide (14.6 g, 103 mmol), and 20 mL of dry
ether in
a 100 mL oven-dried round-bottom flask. The
Grignard solution was cooled in an ice bath, and cyclopropyl
methyl ketone (4.5 g, 53.5 mmol) in 5 mL of ether was added
dropwise over 20 min which produced much foaming. The
reaction flask was removed from the ice bath and stirred for
1 h at room temperature. The flask was then returned to the
ice bath, 30 mL of saturated aqueous ammonium chloride was
added gradually, and the solution was stirred for 15 min. The
almost colorless organic phase was separated, and the aqueous
phase was extracted with 4 × 20 mL of ether. The organic
phases turned orange after the extraction due to the presence
of the small amount of iodine which was used to initiate the
Grignard reaction. The combined organic phases were shaken
with 15 mL of water and a little Na2S2O3 until the color faded.
The organic phase was once again separated and washed with
(13) Christie, E. W.; McKenzie, A.; Ritchie, A. J . Chem. Soc. 1935,
153.