J. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1824–1828
1827
4.2. Preparation of 2-bromo-1-(4-hydroxy-3-
(hydroxymethyl)phenyl)ethanone 3
345.0307 (M+AcOH)+; Anal. Calcd for C12H15BrO3: C, 50.19; H,
5.27. Found: C, 50.16; H, 5.13.
To a solution of 5-(2-bromoacetyl)-2-hydroxybenzaldehyde
(486 mg, 2 mmol) in 10 ml of acetic acid was added sodium boro-
hydride (76 mg, 2 mmol) in three portions at 8–10 °C. The reaction
mixture was then brought to room temperature and the stirring
was continued for another hour. Water (20 ml) was added, and
then the mixture was neutralized with a saturated solution of
potassium bicarbonate. The aqueous solution was extracted twice
with 20 ml of ethyl acetate. The combined organic phase was
washed with brine and dried over magnesium sulfate. The solvent
was removed under reduced pressure to give a crude yellow solid
product. Further purification by recrystallization in mixture of
dichloromethane and n-hexane afforded a white solid product
(85% yield). 1H NMR (DMSO-d6) d: 8.01 (s, 1H), 7.83 (d, J = 8.4 Hz,
1H), 6.91 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H), 4.52 (s, 2H); 13C NMR
(DMSO-d6) d: 19.2, 159.5, 129.7, 129.2, 128.5, 125.2, 114.4, 57.7,
33.3; GC/MS (EI, m/z): 243.9 245.9 (M+); Anal. Calcd for C9H9BrO3:
C, 44.11; H, 3.70. Found: C, 43.97; H, 3.55.
4.5. Preparation of (R)-2,2-dimethyl-6-(oxiran-2-yl)-4H-
benzo[d][1,3]dioxine 6
To a solution of (R)-2-bromo-1-(2,2-dimethyl-4H-benzo[d][1,3]-
dioxin-6-yl)ethanol (287 mg, 1 mmol) in a mixture of THF/MeOH
(2.5 ml/2.5 ml) was added potassium carbonate (414 mg, 3 mmol).
The mixture was filtered after it was stirred vigorously at room tem-
perature for 2 h. The filtrate was concentrated under reduced pres-
sure and further purification was performed by flash column
chromatography on neutralaluminumoxide (petroleumether/ethyl
acetate = 20/1) to give 6 as a yellowish oil (93% yield). ½a D20
¼ ꢁ39:7
ꢀ
(c 1.1, CHCl3); 1H NMR (CDCl3) d: 6.98 (d, J = 8.4 Hz, 1H), 6.82 (s, 1H),
6.79 (d, J = 8.4 Hz, 1H), 4.96 (m, 1H), 4.82 (s, 2H), 3.59 (m, 2H), 1.54 (s,
6H); 13C NMR (CDCl3) d: 150.51, 129.24, 125.67, 123.37, 119.87,
117.55, 99.55, 60.64, 24.63; GC/MS EI m/z: 206.1 (M+); Anal. Calcd
for C12H14O3: C, 69.88; H, 6.84. Found: C, 69.74; H, 6.70.
4.6. Preparation of 4-(6-bromohexyloxy)butylbenzene 7
4.3. Preparation of 2-bromo-1-(2,2-dimethyl-4H-benzo-
[d][1,3]dioxin-6-yl) ethanone 4
To a mixture of 4-phenylbutanol (0.75 g, 5 mmol) and 1,6-
dibromohexane (2.42 g, 10 mmol) were added potassium hydrox-
ide (1.12 g, 20 mmol) and tetra-butylammonium hydrogen sulfate
(0.17 g, 0.5 mmol). After stirring for 20 h at room temperature, the
mixture was filtered and the filtrate was dissolved in 10 ml of
ether. The resulting solution was washed with water and dried
over anhydrous sodium sulfate. The solvent was evaporated under
reduced pressure and the residue was purified by vacuum distilla-
tion to give compound 7 (81% yield). 1H NMR (CDCl3) d: 7.27–7.22
(m, 2H), 7.18–7.16 (m, 3H), 3.42–3.36 (m, 6H), 2.64–2.60 (m, 2H),
1.86–1.79 (m, 2H), 1.68–1.52 (m, 6H), 1.48–1.33 (m, 4H); 13C NMR
(CDCl3) d: 142.4, 128.3, 128.1, 125.6, 70.6, 70.6, 35.6, 32.7, 32.4,
29.5, 29.3, 27.9, 27.2, 25.3; LC/MS (ESI, m/z): 313.2 (M+); Anal.
Calcd for C16H25BrO: C, 61.34; H, 8.04. Found: C, 61.21; H, 7.90.
To a suspension of 2-bromo-1-(4-hydroxy-3-(hydroxymethyl)-
phenyl)ethanone (490 mg, 2 mmol) and p-toluenesulfonic acid
(1.7 mg, 0.01 mmol) in 10 ml of dichloromethane was added drop-
wise 2,2-dimethoxypropane (289 mg, 2.2 mmol) in dichlorometh-
ane (5 ml). The suspension was stirred vigorously until it became
homogeneous. After the reaction was complete, as monitored by
TLC, it was washed with saturated sodium bicarbonate solution
(10 ml). The organic phase was separated and distilled under re-
duced pressure. The residue was purified by flash column chroma-
tography on silica gel (hexane/ethyl acetate = 20/1) to give a
yellowish oil (99% yield). 1H NMR (CDCl3) d: 7.82 (d, J = 8.8 Hz,
1H), 7.68 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.89 (s, 2H), 4.38 (s, 2H),
1.57 (d, J = 1.6 Hz, 6H); 13C NMR (CDCl3) d: 189.9, 156.3, 129.6,
126.5, 126.3, 119.5, 117.7, 100.7, 60.5, 30.6, 24.7; GC/MS (EI, m/
z): 283.9, 285.9 (M+); Anal. Calcd for C12H13BrO3: C, 50.55; H,
4.60. Found: C, 50.40; H, 4.46.
4.7. Preparation of N-benzyl-6-(4-phenylbutoxy)hexan-1-
amine 8
To a mixture of benzylamine (0.321 g, 3 mmol) and triethyl-
amine (0.2 g, 2 mmol) was added sodium iodide (0.015 g,
0.1 mmol). The mixture was stirred at 45 °C for 30 min. Then, 4-
(6-bromohexyloxy)butylbenzene 7 (0.314 g, 1 mmol) was added
drop-wise. The reaction was continued until TLC monitoring
showed the disappearance of bromoether 7. The solvent and excess
amines were evaporated under reduced pressure. Water and
dichloromethane were added to the crude product for extraction
and the organic phase was separated, washed with brine and dried
with anhydrous MgSO4. The filtrate was evaporated to dryness to
give a yellowish oily product. Further purification by flash column
chromatography on silica gel (dichloromethane/methanol = 50/1)
gave the desired product (75% yield). 1H NMR (CDCl3) d: 7.31–
7.29 (m, 4H), 7.25–7.15 (m, 6H), 3.78 (s, 2H), 3.42–3.34 (m, 4H),
2.64–2.59 (m, 4H), 1.96 (br, 1H), 1.63–1.53 (m, 8H), 1.35–1.31
(m, 4H); 13C NMR (CDCl3) d: 142.7, 136.6, 129.8, 129.3, 128.9,
128.7, 128.5, 128.2, 125.9, 71.0, 70.9, 62.4, 55.4, 52.9, 48.4, 36.0,
29.9, 29.6, 28.6, 28.3, 27.0, 26.2; LC/MS (ESI m/z): 340.3 (M+H)+;
Anal. Calcd for C23H33NO: C, 81.37; H, 9.80; N, 4.13. Found: C,
81.24; H, 9.67; N, 4.01.
4.4. Preparation of (R)-2-bromo-1-(2,2-dimethyl-4H-benzo-
[d][1,3]dioxin-6-yl) ethanol 5
A suspension of
g
5-pentamethylcyclopentadienylrhodium di-
mer (3.0 mg, 0.005 mmol) and (S,S)-PEG-BsDPEN (16 mg,
0.012 mmol) in the mixture of PEG-800 (1.8 ml) and H2O (0.2 ml)
was prepared. The mixture was purged with argon and stirred at
40 °C for 1 h. HCOONa (340 mg, 5 mmol) and bromoketone 4
(285 mg, 1 mmol) were added into the preformed catalyst solution.
The mixture was stirred at room temperature for 12 h until the
reaction was complete. Dichloromethane was added and the or-
ganic phase was separated. The combined organic phases were
washed with 2 ml of saturated brine and dried with sodium sulfate.
The organic solvent was removed under reduced pressure. The res-
idue was purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 10/1) to give a white solid prod-
uct. The enantiomeric excess was determined by chiral HPLC with
a Chiracel OD-H column. (Hex/IPA = 90/10, 220 nm). Retention
time: 21.87 min, 24.35 min (major). (93% yield, 98% ee.)
½
a 2D0
ꢀ
¼ ꢁ29:3 (c 1.1, CHCl3); 1H NMR (CDCl3) d: 7.14 (d, J = 8.8 Hz,
1H), 7.00 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.84 (t, J = 3.6 Hz, 1H),
4.82 (s, 2H), 3.63–3.28 (m, 2H), 2.17 (s, 2H), 1.53 (d, J = 1.2 Hz,
6H); 13C NMR (CDCl3) d: 151.2, 132.2, 125.8, 122.3, 119.5, 117.2,
99.7, 73.4, 60.8, 39.9, 24.7, 24.6; GC/MS (EI, m/z): 286.0, 288.0
(M+); HRMS Calcd for C14H19BrO5: 345.0343. Found: (ESI, m/z):
4.8. Preparation of (R)-2-(benzyl(6-(4-phenylbutoxy)hexyl)-
amino)-1-(2,2-dimethyl-4H-benzo[d][1,3] dioxin-6-yl)ethanol 9
The mixture of chiral epoxide 6 (206 mg, 1 mmol) and amine 8
(339 mg, 1 mmol) was heated to 120 °C without an added solvent