10.1002/ejoc.201701811
European Journal of Organic Chemistry
FULL PAPER
3.35-3.30 (m, 2H), 2.97-2.69 (m, 2H), 1.66 (s, 6H) ppm. The
NMR data is completely in accordance with previous literature[9a]
7-methoxy-2,2-dimethyl-6,8-bis(3-methylbut-2-en-1-yl)-5-
phenethyl-4H-1,3-benzodioxin-4-one (9):8 (2.4 g, 5 mmol) was
dissolved in distilled toluene (24 mL) and THF (48 mL) and
cooled to -100oC. n-BuLi (1.6 M, 5.2 mmol, 3.3 mL) was added
to this solution and the mixture was maintained at -100 oC for 25
min. Prepared CuCN•2LiCl (1.5 mL, 1.5 mmol), distilled HMPA
(4.5 mL, 25 mmol) and freshly distilled prenyl bromide (1.56
mL,12.5 mmol) were subsequently added. The resulted solution
was stirred at r.t. After 1 h, the reaction mixture was added a
mixture of NH3•H2O and aqueous NaCl (1:1 v/v) and extracted
with EtOAc (4 x). The organic layer was washed with water and
brine, dried with anhydrous Na2SO4 and concentrated under
reduced pressure. The crude was then subjected to flash
chromatography (hexane/EtOAc = 650:1) to afford 9 (1.12 g.
50%) as a light yellow solid. M.p. 219-220 oC. 1H NMR (300 MHz,
CDCl3): δ = 7.35-7.26 (m, 4H), 7.21-7.19 (m, 1H), 5.13 (t, J = 6.4
Hz, 1H), 5.06 (m, 1H), 3.75 (s, 3H), 3.39 – 3.30 (m, 6H), 2.83 –
2.78 (m, 2H), 1.78 (s, 3H), 1.75 (s, 3H), 1.70 (s, 6H), 1.68 (s, 6H)
ppm.13C NMR (75 MHz, CDCl3): δ = 162.6, 160.6, 155.1, 144.6,
142.5, 131.9, 129.8, 128.7, 128.4, 126.0, 123.8, 122.4, 121.9,
109.2, 104.6, 37.1, 32.6, 25.8, 25.8, 25.3, 23.3, 18.2, 18.0 ppm.
HRMS (ESI): calcd for C29H36O4Na+ [M + Na]+: 471.2506, found:
471.2501.
.
6-bromo-7-methoxy-2,2-dimethyl-5-phenethyl-4H-1,3-
benzodioxin-4-one (6): To the solution of 5 (31.2 mg, 0.1 mmol)
in DCM (1.5 mL) and MeOH (0.75 mL) was added NBS (53.4
mg, 0.3 mmol), allowed to stir at r.t. for 3.5 h. After the complete
conversion of starting material (monitored by TLC), the mixture
was diluted with DCM, washed with aqueous Na2S2O3, water
and brine. The organic layer was then dried by anhydrous
Na2SO4 and concentrated under reduced pressure. The crude
product was subjected to flash chromatography (hexane/EtOAc
= 75:1) to afford 6 (31.5 mg, 80.6%) as a light yellow amorphous
1
solid. H-NMR (300 MHz, CDCl3): δ = 7.41 – 7.17 (m, 5H), 6.40
(s, 1H), 3.93 (s, 3H), 3.66 – 3.61 (m, 2H), 2.89 – 2.83 (m, 2H),
1.68 (s, 6H) ppm. 13C-NMR (75 MHz, CDCl3): δ = 161.4, 159.4,
158.2, 147.2, 141.9, 128.9, 128.4, 126.1, 110.2, 106.3, 105.1,
98.8, 56.8, 36.3, 35.1, 25.7. HRMS (ESI): calcd for
C19H1935BrO4Na+ [M + Na]+: 413.0359, found: 413.0359.
6,8-dibromo-7-methoxy-2,2-dimethyl-5-phenethyl-4H-1,3-
benzodioxin-4-one (7): To the solution of 5 (1.7 g, 5.4 mmol)
and pyridinium 4-toluenesulfonate (8.1 g, 32.1 mmol) in
dichloromethane (80 mL) was added 1,3-dibromo-5,5-
dimethylhydantoin (6.1g, 21.4 mmol). The mixture was stirred at
r.t. in dark overnight. After the complete conversion of the
starting material, the mixture was diluted with DCM, washed with
aqueous Na2S2O3, water and brine. The organic layer was then
dried by anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was subjected to flash
chromatography (hexane/EtOAc = 200:1) to afford 7 (2.2 g,
86%) as a light yellow amorphous solid.1H NMR (300 MHz,
CDCl3): δ = 7.39 – 7.18 (m, 5H), 3.96 (s, 3H), 3.63 – 3.58 (m,
2H), 2.90 – 2.84 (m, 2H), 1.72 (s, 6H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.9, 158.6, 154.5, 146.2, 141.4, 128.7, 128.5,
126.2, 116.7, 110.8, 106.0, 105.6, 60.8, 36.4, 34.9, 25.7 ppm.
HRMS (ESI): calcd for C19H1835Br37BrO4Na+ [M + Na]+: 492.9444,
found: 492.9443.
2-hydroxy-4-methoxy-3,5-bis(3-methylbut-2-en-1-yl)-6-
phenethylbenzoic acid (Amorfrutin C): To the solution of 9
(1.12 g, 2.5 mmol) in THF (10 mL) and H2O (10 mL) was added
LiOH·H2O (420 mg ,40 mmol). Then the mixture was heated to
reflux overnight. The reaction mixture was then cooled to r.t. and
diluted with EtOAc. 1M HCl was added to acidified the solution
to slightly acid (pH = 2 ~ 3). The organic layer was separated
and the water layer was extracted with EtOAc (3 x). Then the
organic layer was mixed and washed with water and brine, dried
with anhydrous Na2SO4 and concentrated under reduced
pressure. The crude was then subjected to flash
chromatography (hexane/EtOAc
=
10:1
~
5:1) to afford
o
Amorfrutin C (1.01 g, 99%) as a white solid. M.p. 220-222 C.
1H NMR (500 MHz, methanol-d4): δ = 7.23 (t, J = 7.4 Hz, 2H),
7.19 – 7.17 (m, 2H), 7.13 (t, J = 7.2 Hz, 1H), 5.24 (t, J = 6.6 Hz,
1H), 5.02 (m, 1H), 3.66 (s, 3H), 3.36 - 3.33 (m, 4H), 3.25 – 2.98
(m, 2H), 2.78 – 2.76 (m, 2H), 1.77 (s, 3H), 1.70 (s, 3H), 1.67 (s,
3H), 1.65 (s, 3H) ppm.13C NMR (126 MHz, methanol-d4): δ =
174.9, 162.6, 161.8, 143.7, 143.5, 132.0, 131.9, 129.2, 129.2,
126.9, 126.8, 125.7, 124.3, 122.0, 110.7, 61.9, 38.7, 34.3, 26.3,
25.9, 25.8, 24.3, 18.2, 18.0 ppm. HRMS (ESI): calcd for
C26H32O4Na+[M + Na]+: 431.2193, found: 431.2190.
8-bromo-7-methoxy-2,2-dimethyl-6-(3-methylbut-2-en-1-yl)-
5-phenethyl-4H-1,3-benzodioxin-4-one (8): 7 (1.8 g, 3.8 mmol)
was dissolved in distilled toluene (18 mL) and THF (36 mL) and
cooled to -100 oC. n-BuLi (1.6 M, 4 mmol, 2.5 mL) was then
added to this solution and the mixture was maintained at -100 oC
for 30 min. Prepared CuCN•2LiCl (1.17 mL, 1.17 mmol)[19] and
freshly distilled prenyl bromide (1.17 mL, 9.4 mmol) was
subsequently added. The resulted solution was stirred at r.t.
After 1 h, the reaction mixture was added a mixture of NH3•H2O
and aqueous NaCl (1:1 v/v) and extracted with EtOAc (4 x). The
organic layer was washed with water and brine, dried with
anhydrous Na2SO4 and concentrated under reduced pressure.
The crude was then subjected to flash chromatography
(hexane/EtOAc = 500:1) to afford 8 (1.27 g. 72%) as a light
yellow solid. M.p.: 210-211 C H NMR (300 MHz, CDCl3): δ =
7.34 – 7.10 (m, 5H), 5.01 (t, J = 6.9 Hz, 1H), 3.80 (s, 3H), 3.52 –
3.46 (m, 2H), 3.27 (d, J = 7.0 Hz, 2H), 2.82 – 2.76 (m, 2H), 1.70
(s, 3H), 1.61 (s, 3H), 1.59 (s, 6H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.7, 159.6, 155.7, 144.6, 142.0, 132.7, 128.8,
128.5, 126.1, 124.0, 121.5, 116.3, 110.4, 105.1, 61.4, 36.5, 35.2,
25.8, 25.7, 23.7, 18.1 ppm. HRMS (ESI): calcd for
C24H2735BrO4Na+[M + Na]+: 481.0985, found: 481.0985.
7-methoxy-2,2-dimethyl-6-(3-methylbut-2-en-1-yl)-5-
phenethyl-4H-1,3-benzodioxin-4-one (10): 6 (98 mg, 0.25
mmol) was dissolved in distilled toluene (1.2 mL) and THF (2.5
o
mL) and cooled to -100 C. n-BuLi (1.6 M, 0.26 mmol, 164 μl)
o
was added to this solution at -100 C and the resulted reaction
mixture was stirred at -100oC for 30min. Prepared CuCN•2LiCl
(78 μL, 0.075 mmol) and freshly distilled prenyl bromide (78 μL,
0.625 mmol) was subsequently added. The resulted solution
was stirred at r.t. After 1 h, the reaction mixture was added a
mixture of NH3•H2O and aqueous NaCl (1:1 v/v) and extracted
with EtOAc (4 x). The combine organic layer was washed with
water and brine, dried with anhydrous Na2SO4 and concentrated
under reduced pressure. The crude was then subjected to flash
chromatography (hexane/EtOAc = 500:1) to afford 10 (68 mg.
o
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