Patel et al.
SCHEME 9. Confirmation of the Retention of
(2R,4′R,8′R)-Stereochemistry upon Nitration of γ-Tocopherol
(3)
was washed with water, saturated aqueous NaHCO3 solution, and
again with water, dried over MgSO4, and concentrated in vacuo.
The yellow, oily residue was crystallized from light petroleum ether
to give 6-acetyl-2,2,8-trimethylchroman as an off-white solid (1.02
g, 70%): mp ) 60-62 °C; TLC Rf ) 0.30 (n-hexane/diethyl ether,
1
v/v ) 7:3), orange color with p-anisaldehyde reagent; H NMR δ
3
1.28 (s, 6H, H-2a), 1.75 (t, 2H, J ) 6.76 Hz, H-3), 2.12 (s, 3H,
3
H-8b), 2.45 (s, 3H, -COCH3), 2.74 (t, 2H, J ) 6.76 Hz, H-4),
7.51 (s, 1H, Ar-H), 7.53 (s, 1H, Ar-H); 13C NMR δ 16.08 (C-
8b), 22.52 (C-4), 26.21 (CH3CO), 27.08 (C-2a, d.i.), 32.53 (C-3),
75.31 (C-2), 119.86, 126.30, 128.26, 128.56, 128.91 (C-4a, C-5,
C-6, C-7, C-8), 156.84 (C-8a), 197.30 (CO).
6-Acetoxy-2,2,8-trimethylchroman. Into a mixture of 6-acetyl-
2,2,8-trimethylchroman (0.47 g, 2.16 mmol), glacial acetic acid
(3.75 mL), and water (0.70 mL) was added peracetic acid (∼39%
in acetic acid, 0.70 mL) at rt. The mixture was left standing
overnight and then poured into water. Residual peracid was
decomposed with sodium hydrogensulfite. The reaction mixture was
extracted with ethyl acetate and subsequently washed with water,
saturated aqueous NaHCO3 solution, and again water, dried over
MgSO4, and concentrated in vacuo. The yellow, oily residue
obtained was purified by flash chromatography (n-hexane with a
few drops of diethyl ether) to afford 6-acetoxy-2,2,8-trimethyl-
chroman as a colorless viscous liquid (0.31 g, 60%): TLC Rf )
4.1.2. Synthesis of γ-Tocopherol Model Compound 7. 6-Hy-
droxy-2,2,7,8-tetramethylchroman (7). A solution of 2-methyl-
3-buten-2-ol (10.81 mmol, 1.13 mL) in THF (0.93 mL) was added
dropwise to a solution of 2,3-dimethyl-1,4-hydroquinone (1.50 g,
10.85 mmol) in formic acid (14.0 mL, 98-100%) and THF (3.7
mL), under stirring at 100 °C. The addition was completed within
1 h. Stirring was continued for additional 3 h, and the cooled
mixture was poured onto crushed ice.
1
0.34 (n-hexane/diethyl ether, v/v ) 8:2); H NMR δ 1.39 (s, 6H,
H-2a), 1.84 (t, 2H, 3J ) 6.77 Hz, H-3), 2.21 (s, 3H, H-8b), 2.32 (s,
3H, acetyloxy), 2.81 (t, 2H, 3J ) 6.74 Hz, H-4), 6.70 (s, 1H, Ar-
H), 6.74 (s, 1H, Ar-H); 13C NMR δ 16.10 (C-8b), 21.07 (CH3,
acetyloxy), 22.76 (C-4), 27.05 (C-2a, d.i.), 32.57 (C-3), 74.04 (C-
2), 119.04, 120.70, 121.12, 127.28 (C-4a, C-5, C-7, C-8), 142.50
(C-6), 149.85 (C-8a), 170.20 (COO, acetyloxy).
Water was added, and the mixture was extracted with diethyl
ether. Light petroleum ether (10 mL) was added to the combined
ethereal extracts, and the mixture was washed with water. This way,
most of the formic acid contained in the ether phase was removed.
The solvent was evaporated, and the residue was dissolved in
methanol (14 mL). Concentrated HCl (0.18 mL) was added, and
the solution was heated at 60 °C for 20 min to hydrolyze any
formate ester that might have formed. The methanol was evaporated,
and the residue was dissolved in diethyl ether (10 mL). After
washing with water, with saturated aqueous solution of NaHCO3,
and again with water and drying over MgSO4, the mixture was
concentrated in vacuo. The residue was triturated with light
petroleum under reflux (40 mL) for 15 min. After cooling to rt,
nonreacted 2,3-dimethyl-1,4-hydroquinone (∼15%) was filtered off
and the filtrate was concentrated in vacuo, followed by flash
chromatography (gradient light petroleum ether/diethyl ether v/v
) 9:2 f v/v ) 9:0.8) to provide a light brown solid (7) in 30%
yield:15,30,33 mp ) 75-77 °C; TLC Rf ) 0.35 (light petroleum ether/
6-Hydroxy-2,2,8-trimethylchroman (8). Procedure A: Into the
ice-cooled solution of acetoxy-2,2,8-trimethylchroman (2.66 g,
11.38 mmol) in dry methanol (120 mL) was added dropwise a 0.1
M sodium methanolate in methanol (0.1 M, 2.0 equiv, 228 mL,
22.8 mmol), and the mixture was stirred for 15 min at rt. After
completion of the reaction (TLC control), the mixture was diluted
with methanol, and strongly acidic cation exchange resin (Dowex
50WX8) was added until neutralization. The mixture was filtered,
and the filtrate concentrated in vacuo. The residue was purified by
flash chromatography (gradient n-hexane/diethyl ether v/v ) 6:1.5
f v/v ) 6:1) and recrystallization from n-hexane to afford
6-hydroxy-2,2,8-trimethylchroman (8) as a colorless solid in 97%
yield. Procedure B: A suspension of LiAlH4 (47.7 mg, 1.25 mmol)
in dry diethyl ether (2.8 mL) was refluxed (bath temperature
42 °C) for an hour. 6-Acetoxy-2,2,8-trimethylchroman (0.27 g,
1.18 mmol) dissolved in dry diethyl ether (0.7 mL) was added
dropwise under stirring at reflux. The addition was completed within
1 h, the stirring was continued for 2 h, and the mixture was cooled
to rt. Excess hydride was destroyed by the dropwise addition of
wet diethyl ether. The mixture was refluxed for another 10 min
and cooled to rt. At this stage, there should be no gray, nonreacted
LiAlH4 remaining and the precipitate should be bright white. The
reaction mixture was neutralized with 5% aqueous H2SO4 solution,
and phases were separated. The organic layer was washed with
water, with saturated aqueous NaHCO3 solution, again with water,
dried over MgSO4, and evaporated in vacuo. The remaining pale
brown, oily residue was purified as described in procedure A (88%):
1
diethyl ether, v/v ) 8:2); H NMR δ 1.29 (s, 6H, H-2a), 1.74 (t,
3
2H, J ) 6.8 Hz, H-3), 2.10 (s, 3H, H-7a/8b), 2.13 (3H, S, H-8b/
7a), 2.68 (t, 2H, 3J ) 6.8 Hz, H-4), 4.0 (br, 1H, OH), 6.37 (s, 1H,
H-5); 13C NMR δ 11.85, 11.89 (C-7a, C-8b), 22.63 (C-4), 26.94
(C-2a), 32.93 (C-3), 73.39 (C-2), 112.13 (C-5), 118.05 (C-4a),
121.61 (C-7), 125.76 (C-8), 145.85 (C-8a), 146.25 (C-6); IR (KBr)
3271, 2979, 2927, 2359, 1619, 1420, 1253, 1208 cm-1
.
Also, slightly yellowish crystals of the bisalkylated product
3,3,5,6,8,8-hexamethyl-1,2,3,8,9,10-hexahydropyrano[3,2-f]-
chromene were found (10%). Anal. Calcd for C18H26O2: C, 78.79;
H, 9.55; O, 11.66. Found: C, 78.88; H, 9.56.
Compound 7 was recrystallized from n-hexane with some drops
of ethyl acetate to obtain crystals suitable for X-ray crystallography.
4.1.3. Synthesis of δ-Tocopherol Model Compound 8. 6-Acetyl-
2,2,8-trimethylchroman. 2-Methyl-3-buten-2-ol (26.6 mmol, 2.29
g, 4 equiv) was added dropwise to a solution of 4-hydroxy-3-
methylacetophenon (1.00 g, 6.65 mmol) in iso-propylether (10 mL)
and concd H2SO4 (0.33 mL), under stirring at reflux (55-58 °C).
The addition was completed within 3 h, and the mixture was further
stirred for additional 3 h. After cooling to rt, the reaction mixture
34
mp 81-82 °C; TLC Rf ) 0.34 (n-hexane/diethyl ether, v/v )
1
3
6:4); H NMR δ 1.21 (s, 6H, H-2a), 1.66 (t, 2H, J ) 6.8 Hz,
H-3), 2.03 (s, 3H, H-8b), 2.60 (t, 2H, 3J ) 6.8 Hz, H-4), 4.66 (br,
1H, OH), 6.30 (d, 1H, J ) 2.9 Hz, H-7), 6.38 (d, 1H, J ) 2.9
Hz, H-5); 13C NMR δ 16.02 (C-8b), 22.80 (C-4), 26.89 (C-2a),
32.84 (C-3), 73.54 (C-2), 112.64 (C-5), 115.68 (C-7), 121.07 (C-
4
4
(34) Nakamura, T.; Kijima, S. Chem. Pharm. Bull. 1972, 20, 1297-
1304.
6510 J. Org. Chem., Vol. 72, No. 17, 2007