Antioxidant Profile of all-rac-R-Selenotocopherol
and dichloromethane, and the aqueous phase was extracted with
dichloromethane. The combined organic phase was washed with
brine, dried over MgSO4, and evaporated to give the title compound
acetic acid (3.5 mL) was heated at 154 °C for 30 min in a
microwave reactor. The product was precipitated with water, and
the supernatant was decanted. The crude solid was dissolved in
ether, washed with water and saturated brine, and dried over
MgSO4, and the solvent was removed in vacuo to give a crude
brown solid. This was purified by column chromatography (pentane/
dichloromethane 9:1) to give the title compound (554 mg, 57%)
1
(2.46 g, quantitive) as a beige solid: mp 59-60 °C; H NMR δ
7.17 (1H, s), 3.69 (3H, s), 2.43 (3H, s), 2.24 (3H, s), 2.23 (3H, s);
13C NMR δ 157.3, 137.2, 136.2, 132.7, 129.2, 118.6, 111.1, 60.4,
20.0, 14.6, 13.1. Anal. Calcd for C11H13NO: C, 75.40; H, 7.48.
Found: C, 75.22; H, 7.47.
1
as a white crystalline solid: mp 101-102 °C; H NMR δ 4.87
(2H, s), 3.66 (3H, s), 2.41 (3H, s), 2.40 (3H, s), 2.28 (3H, s); 13C
NMR δ 156.4, 136.3, 133.9, 132.4, 130.0, 123.9, 60.5, 45.7, 21.0,
14.3, 12.9. Anal. Calcd for C11H14BrClO: C, 47.60; H, 5.08.
Found: C, 47.75; H, 5.02.
C. 3-Methoxy-2,4,5-trimethylbenzoic Acid (15). A mixture of
nitrile 14 (1.0 g, 5.7 mmol), KOH (960 mg, 17.1 mmol), water
(1.4 mL), and ethylene glycol (11 mL) was heated (bath temp of
140 °C) for 7 h. The solution was then cooled to room temperature
and treated with aqueous HCl (24 mL, 1 M). The precipitated solid
was collected by filtration and dried under vacuum over P2O5,
giving the title compound (1.0 g, 90%) as a white powder: mp
159-160 °C; 1H NMR δ 11.70 (1H, br s), 7.65 (1H, s), 3.69 (3H,
s), 2.55 (3H, s), 2.28 (3H, s), 2.26 (3H, s); 13C NMR δ 173.2, 157.7,
135.9, 135.7, 131.8, 128.4, 127.1, 60.4, 20.1, 13.8, 13.2. Anal. Calcd
for C11H14O3: C, 68.02; H, 7.27. Found: C, 67.88; H, 7.23.
D. 3-Methoxy-2,4,5-trimethylbenzyl Alcohol (16). To a solution
of the acid 15 (981 mg, 5.05 mmol) in dry THF (11 mL) at 0 °C
under nitrogen was added LiAlH4 (383 mg, 10.1 mmol) portionwise.
After complete addition, the mixture was allowed to come to room
temperature for 30 min and then heated at reflux for 20 h. Excess
LiAlH4 was quenched by careful addition of aqueous HCl (3 M)
at 0 °C, and the aqueous phase was extracted with Et2O. The
combined organic phase was washed with brine, dried over MgSO4,
and evaporated to give the title compound (880 mg, 97%) as a
white powder: mp 87-88 °C; 1H NMR δ 6.94 (1H, s), 4.63 (2H,
s), 3.68 (3H, s), 2.27 (3H, s), 2.25 (3H, s), 2.20 (3H, s), 1.51 (1H,
br s); 13C NMR δ 157.2, 137.4, 135.7, 129.4, 126.7, 125.4, 64.0,
60.3, 20.1, 12.6, 11.5. Anal. Calcd for C11H16O2: C, 73.30; H, 8.95.
Found: C, 73.42; H, 8.99.
E. 3-Methoxy-2,4,5-trimethylbenzyl Bromide (17). Neat PBr3
(710 mg, 2.6 mmol) was added dropwise to a solution of alcohol
16 (860 mg, 4.77 mmol) in Et2O (10 mL). The reaction mixture
was stirred at room temperature for 4.5 h, before quenching with
water. The organic phase was diluted with Et2O, washed with water
and brine, dried over MgSO4, and evaporated to give the title
compound (1.13 g, 97%) as a pale-blue powder: mp 70-71 °C;
1H NMR δ 6.93 (1H, s), 4.49 (2H, s), 3.68 (3H, s), 2.32 (3H, s),
2.23 (3H, s), 2.20 (3H, s); in good agreement with previously
published data;23 13C NMR δ 157.4, 136.0, 134.3, 130.9, 127.9,
127.2, 60.4, 33.3, 20.0, 12.8, 11.7. Anal. Calcd for C11H15BrO: C,
54.34; H, 6.22. Found: C, 54.23; H, 6.16.
I. tert-Butyl-2-(2-bromo-5-methoxy-3,4,6-trimethylbenzyl) Ac-
etoacetate (20). Neat tert-butyl acetoactetate (475 mg, 3 mmol)
was added dropwise to a stirred slurry of NaH (60% in mineral
oil, 120 mg, 3 mmol) in dry THF (4 mL) at 0 °C under nitrogen.
The mixture was allowed to come to room temperature over 30
min, and the solution became homogeneous. The benzyl chloride
9b (278 mg, 1 mmol) dissolved in THF (3 mL) was added by
syringe, and the mixture was heated at reflux for 15 h. The reaction
was then allowed to cool to room temperature and was quenched
by addition of saturated aqueous NH4Cl. The aqueous phase was
extracted with ether, and the combined organic phase was washed
with brine, dried over MgSO4, and evaporated to give crude product.
Excess tert-butyl acetoactetate was removed by Kugelrohr distil-
lation under vacuum, and the residue was subjected to column
chromatography (pentane/Et2O 85:15) to give the title compound
as a colorless viscous oil (311 mg, 78%): 1H NMR δ 3.93 (1H, t,
J ) 7.3 Hz), 3.60 (3H, s), 3.39 (1H, dd, J ) 14.5, 7.3 Hz), 3.32
(1H, dd, J ) 14.5, 7.3 Hz), 2.37 (3H, s), 2.27 (3H, s), 2.25 (3H, s),
2.17 (3H, s), 1.37 (9H, s); 13C NMR δ 203.4, 168.9, 156.3, 135.8,
135.4, 129.8, 129.6, 124.2, 82.1, 60.3, 59.6, 31.9, 30.0, 28.0, 21.0,
14.1, 13.8. Anal. Calcd for C19H27BrO4: C, 57.15; H, 6.82.
Found: C, 57.12; H, 6.95.
J. 4-(2-Bromo-5-methoxy-3,4,6-trimethylphenyl)-2-butanone
(21). A solution of acetoacetate 20 (5.0 g, 12.5 mmol) in aqueous
HCl (9 M, 80 mL) was heated at reflux for 15 h. The mixture was
then cooled to room temperature and extracted with diethyl ether.
The organic phase was washed with water and saturated brine and
then dried over MgSO4 to give the title compound (3.65 g, 98%)
1
as a white solid: mp 84-85 °C; H NMR δ 3.63 (3H, s), 3.09
(2H, m), 2.64 (2H, m), 2.38 (3H, s), 2.26 (3H, s), 2.25 (3H, s),
2.19 (3H, s); 13C NMR δ 208.3, 156.3, 137.5, 135.8, 129.4, 128.3,
123.7, 60.4, 42.5, 30.1, 28.7, 21.0, 14.1, 13.2. Anal. Calcd for
C14H19BrO2: C, 56.20; H, 6.40. Found: C, 56.31; H, 6.43.
K. 2-[2-(2-Bromo-5-methoxy-3,4,6-trimethylphenyl)ethyl]-2-
methyl-1,3-dioxolane (22). A mixture of ketone 21 (910 mg, 3.0
mmol), p-toluenesulfonic acid (60 mg, 0.3 mmol), and ethylene
glycol (380 mg, 6.1 mmol) in benzene (15 mL) was heated at reflux
for 13 h. The solution was then cooled to room temperature, diluted
with diethyl ether, washed with saturated aqueous NaHCO3 and
brine, dried over MgSO4, and evaporated to give the title compound
as a colorless oil (1.04 g, quantitive): 1H NMR δ 4.04 (4H, s),
3.67 (3H, s), 2.96 (2H, m), 2.41 (3H, s), 2.33 (3H, s), 2.28 (3H, s),
1.86 (2H, m), 1.46 (3H, s); 13C NMR δ 156.2, 138.6, 135.6, 128.9,
128.2, 123.8, 110.0, 65.0, 60.4, 37.5, 29.3, 23.9, 21.0, 14.1, 13.1.
L. 2-[2-(2-Benzylselenenyl-5-methoxy-3,4,6-trimethylphenyl)-
ethyl]-2-methyl-1,3-dioxolane (23). To a solution of the arylbro-
mide 22 (2.74 g, 8.0 mmol) in dry THF (80 mL) at -78 °C under
nitrogen was added t-BuLi (8.4 mL, 8.0 mmol). The mixture was
stirred at -78 °C for 5 min, and then finely ground selenium (662
mg, 8.4 mmol) was added in one portion. The mixture was allowed
to approach room temperature for 15 min until all selenium had
dissolved. Benzyl bromide (1.14 mL, 9.6 mmol) was added, and
the reaction mixture was stirred at room temperature for a further
3 h and then quenched by addition of saturated aqueous NH4Cl.
The aqueous phase was extracted with ether, and the combined
organic phase was washed with brine, dried over MgSO4, and
evaporated to give crude product. This was purified by flash
F. 2-Bromo-5-methoxy-3,4,6-trimethylbenzyl Bromide (9a).
Bromine (750 mg, 4.7 mmol) dissolved in dichloromethane (8 mL)
was added dropwise to a solution of aromatic 17 (1.09 g, 4.5 mmol)
in dichloromethane (10 mL), and the reaction mixture was stirred
for 4.5 h at room temperature. Excess bromine was destroyed by
addition of saturated aqueous Na2S2O3 (20 mL). The aqueous phase
was extracted with dichloromethane, and the combined organic
phase was washed with brine, dried over MgSO4, and evaporated
to give the title compound (1.44 g, quantitative) as a white
1
powder: mp 103-104 °C; H NMR δ 4.77 (2H, s), 3.66 (3H, s),
2.39 (6H, s), 2.27 (3H, s); 13C NMR δ 156.4, 136.4, 133.9, 132.3,
129.9, 123.9, 60.5, 33.9, 21.0, 14.3, 12.9. Anal. Calcd for C11H14-
Br2O: C, 41.03; H, 4.38. Found: C, 41.05; H, 4.31.
G. 4-Bromo-2,3,6-trimethylanisole (19). Anisole 19 was pre-
pared by the same method as that used for anisole 14, using phenol
1
188 as starting material: quantitative yield; H NMR δ 7.28 (1H,
s), 3.70 (3H, s), 2.36 (3H, s), 2.29 (3H, s), 2.27 (3H, s); 13C NMR
δ 156.3, 135.2, 131.9, 131.7, 130.1, 120.0, 60.2, 20.0, 16.0, 13.8.
H. 2-Bromo-5-methoxy-3,4,6-trimethylbenzyl Chloride (9b).
A mixture of anisole 19 (800 mg, 3.5 mmol), paraformaldehyde
(524 mg, 17.5 mmol), concentrated HCl (37%, 7 mL), and glacial
(23) Gruter, G. -J. M.; Akkerman, O. S.; Bickelhaupt, F. J. Org. Chem.
1994, 59, 4473.
J. Org. Chem, Vol. 71, No. 3, 2006 1037