Biomimetic Approach to Dihydrobenzofuran Synthesis
J . Org. Chem., Vol. 66, No. 15, 2001 4971
2H) ppm; 13C NMR (CD3OD) 188.9, 183.5, 160.3, 148.3, 133.2,
108.6, 61.0, 33.4 ppm.
2,3-Dih yd r o-5-h yd r oxy-6-m eth ylben zofu r a n (14d ): Rf
) 0.51 (50% EtOAc/hexanes). IR (neat) ν 3321 br, 2920, 1439,
1265, 1183, 1005, 868 cm-1; 1H NMR (CD3OD) δ 6.61 (s, 1H),
6.44 (s, 1H), 4.41 (t, J ) 8.6 Hz, 2H), 3.07 (t, J ) 8.6 Hz, 2H),
2.10 (s, 3H) ppm; 13C NMR (CD3OD) δ 156.9, 152.6, 128.3,
127.1, 115.0, 114.1, 74.5, 33.5, 19.0 ppm. Anal. Calcd for
C9H10O2: C, 71.98; H, 6.71. Found: C, 71.69; H, 6.58.
2-(2′-H y d r o x y e t h y l)-5-m e t h y l-1,4-b e n z o q u i n o n e
(10d ): Rf ) 0.22 (70% EtOAc/hexanes); IR (neat) ν 3483 br,
1
1652 cm-1; H NMR (CD3OD) 6.64 (br s, 1H), 6.62 (br s, 1H),
3.70 (t, J ) 6.5 Hz, 2H), 2.60 (dt, J ) 6.5, 1.4 Hz, 2H), 2.00 (s,
3H) ppm.
2,3-Dih yd r o-6-br om o-5-h yd r oxyben zofu r a n (14e): Rf )
5-Br om o-2-(2′-h yd r oxyeth yl)-1,4-ben zoqu in on e (10e):
Rf ) 0.24 (50% EtOAc/hexanes); IR (neat) ν 3525 br, 1654, 1590
0.47 (50% EtOAc/hexanes). IR (neat) ν 3297 br, 1531, 1491,
1
1235, 860 cm-1; H NMR (CDCl3) δ 6.86 (s, 1H), 6.85 (s, 1H),
1
cm-1; H NMR (CDCl3) 7.26 (s, 1H), 6.85 (s, 1H), 3.81 (t, J )
5.10 (br s, 1H, exchanges with D2O), 4.52 (t, J ) 8.6 Hz, 2H),
3.12 (t, J ) 8.6 Hz, 2H) ppm; 13C NMR (CDCl3) δ 154.2, 146.2,
128.4, 112.2, 111.7, 107.7, 71.7, 29.9 ppm. Anal. Calcd for C8H7-
BrO2: C, 44.68; H, 3.28. Found: C, 44.93; H, 3.36.
6.0 Hz, 2H), 3.39 (br s, 1H, exchanges with D2O), 2.66 (br t, J
) 6.0 Hz, 2H) ppm; 13C NMR (CDCl3) 185.1, 179.5, 146.7,
138.2, 137.4, 133.5, 60.5, 32.2 ppm.
2-(2′-H yd r oxyet h yl)-5-m et h ylca r b oxyla t e-1,4-b en zo-
qu in on e (10f): Rf ) 0.33 (70% EtOAc/hexanes); IR (neat) ν
3423 br, 1739, 1663 cm-1; 1H NMR (CD3OD) 6.83 (s, 1H), 6.71
(s, 1H), 3.67 (t, J ) 6.3 Hz, 2H), 3.34 (s, 3H), 2.55 (t, J ) 6.5
Hz, 2H) ppm.
2-(2′-H y d r o x y e t h y l)-6-m e t h o x y -1,4-b e n zo q u in o n e
(10g): Rf ) 0.24 (70% EtOAc/hexanes); IR (neat) ν 3493 br,
1676, 1649 cm-1; 1H NMR (CDCl3) 6.63 (br s, 1H), 5.90 (d, J )
2.2 Hz, 1H), 3.83 (m, 5H), 2.71 (t, J ) 6.1 Hz, 2H), 2.01 (br s,
1H, exchanges with D2O) ppm; 13C NMR (CDCl3) 187.3, 182.2,
158.7, 144.0, 134.6, 107.6, 60.5, 32.2 ppm.
Meth yl 2,3-Dih yd r o-5-h yd r oxyben zofu r a n -6-yl ca r box-
yla te (14f): Rf ) 0.42 (70% EtOAc/hexanes). IR (neat) ν 3419
1
br, 2956, 1674, 1625, 1443, 1225, 1053 cm-1; H NMR (CD3-
OD) δ 7.19 (s, 1H), 6.73 (s, 1H), 3.90 (s, 3H), 3.76 (t, J ) 6.8
Hz, 2H), 2.82 (t, J ) 6.8 Hz, 2H) ppm; 13C NMR (CD3OD) δ
171.6, 156.0, 149.2, 137.3, 120.0, 115.0, 111.4, 62.4, 52.6, 35.3
ppm. Anal. Calcd for C10H12O5: C, 56.60; H, 5.70. Found: C,
56.60; H, 5.54.
2,3-Dih yd r o-5-h yd r oxy-7-m eth oxyben zofu r a n (14g): Rf
) 0.43 (50% EtOAc/hexanes). IR (neat) v 3406 br, 2958, 1626,
1
1456, 1344, 1189, 1085 cm-1; H NMR (CD3OD) d 6.28 (br s,
2-(2′-H y d r o x y e t h y l)-6-m e t h y l-1,4-b e n z o q u i n o n e
(10h ): Rf ) 0.23 (50% EtOAc/hexanes); IR (neat) ν 3485 br,
1H), 6.25 (br s, 1H), 4.47 (t, J ) 8.6 Hz, 2H), 3.77 (s, 3H), 3.10
(t, J ) 8.6 Hz, 2H) ppm; 13C NMR (CD3OD) d 155.6, 148.2,
145.2, 132.2, 107.2, 103.5, 74.8, 59.1, 34.1 ppm. Anal. Calcd
for C9H10O3: C, 65.05; H, 6.07. Found: C, 65.31; H, 5.86.
2,3-Dih yd r o-5-h yd r oxy-7-m eth ylben zofu r a n (14h ): Rf
) 0.40 (50% EtOAc/hexanes). IR (neat) ν 3416 br, 1631, 1479,
1197, 935 cm-1; 1H NMR (CD3OD) δ 6.47 (s, 1H), 6.34 (s, 1H),
4.43 (t, J ) 8.6 Hz, 2H), 3.08 (t, J ) 8.6 Hz, 2H), 2.07 (s, 3H)
ppm; 13C NMR (CD3OD) δ 152.9, 152.0, 128.2, 120.4, 116.2,
110.3, 71.7, 31.4, 15.4 ppm. Anal. Calcd for C9H10O2: C, 71.98;
H, 6.71. Found: C, 71.86; H, 6.97.
2,3-Dih ydr o-5-m eth oxy-ben zofu r an o-4,7-qu in on e (14i′):
Rf ) 0.24 (70% EtOAc/hexanes). IR (neat) v 1650, 1627, 1582,
1410, 1249, 1054 cm-1; 1H NMR (CD3OD) δ 5.74 (s, 1H), 4.83
(t, J ) 9.7 Hz, 2H), 3.90 (s, 3H), 2.98 (t, J ) 9.7 Hz, 2H) ppm;
13C NMR (CD3OD) δ 183.2, 176.5, 167.8, 162.8, 116.4, 103.7,
76.8, 57.8 ppm. Anal. Calcd for C9H8O4: C, 60.00; H, 4.48.
Found: C, 60.29; H, 4.26.
1
1657, 1614 cm-1; H NMR (CD3OD) 6.60-6.57 (m, 2H), 3.71
(t, J ) 6.0 Hz, 2H), 2.63 (br t, J ) 6.0 Hz, 2H), 2.03 (s, 3H)
ppm; 13C NMR (CD3OD) 189.2, 188.8, 147.7, 147.6, 134.9,
133.9, 60.9, 33.6, 16.0 ppm.
3,6-Dim et h oxy-2-(2′-h yd r oxyet h yl)-1,4-b en zoq u in on e
(10i): Rf ) 0.21 (70% EtOAc/hexanes); IR (neat) ν 3485 br,
1651, 1602 cm-1; 1H NMR (CD3OD) 5.86 (s, 1H), 4.04 (s, 3H),
3.80 (s, 3H), 3.57 (t, J ) 6.8 Hz, 2H), 2.66 (t, J ) 6.8, 2H)
ppm; 13C NMR (CD3OD) 184.7, 183.9, 160.3, 158.4, 127.3,
106.6, 62.0, 61.1, 57.1, 27.6 ppm.
6-Ch lor o-2-(2′-h yd r oxyet h yl)-1,4-b en zoq u in on e (10j):
Rf ) 0.25 (50% EtOAc/hexanes); IR (neat) ν 3511 br, 1675, 1657
1
cm-1; H NMR (CD3OD) 7.03 (br s, 1H), 6.70 (br s, 1H), 3.73
(t, J ) 6.1 Hz, 2H), 2.68 (t, J ) 6.1, 2H) ppm; 13C NMR (CD3-
OD) 186.5, 180.8, 147.7, 145.1, 135.2, 134.5, 60.6, 34.0 ppm.
Gen er a l P r oced u r e for th e F or m a tion of 2,3-Dih y-
d r oben zofu r a n s (14). To a solution of 98 mg (0.50 mmol) of
hydroxyquinone 10a in PhCH3 (10.0 mL) was added 25 mg
(0.10 mmol) of PPTS followed by 55 mg (0.50 mmol) of DHQ,
and the reaction mixture was refluxed under a nitrogen
atmosphere. The solution was concentrated and purified using
flash chromatography (20 g of SiO2, 15% EtOAc/hexanes) to
provide 71 mg (79%) of the dihydrobenzofuran 14a as a pale
yellow oil.
3-Br om o-6-(2′-h yd r oxy)eth yl-1,4-d ih yd r oben zoqu in o-
n e (DH10e): Rf ) 0.13 (50% EtOAc/hexanes). IR (neat) ν 3321
br, 1501, 1433, 1194, 1032, 801 cm-1; 1H NMR (CD3OD) δ 6.86
(s, 1H), 6.67 (s, 1H), 3.71 (t, J ) 6.8 Hz, 2H), 2.72 (t, J ) 6.8
Hz, 2H) ppm; 13C NMR (CD3OD) δ 150.2, 147.9, 127.5, 119.9,
108.0, 62.8, 34.8 ppm. Anal. Calcd for C8H9BrO3: C, 41.23; H,
3.89. Found: C, 41.47; H, 3.84.
5,5′-Dih yd r oxy-7,7′-d im e t h oxy-4,4′-b i-2,2′,3,3′-d ih y-
d r oben zofu r a n (15g): Rf ) 0.23 (50% EtOAc/hexanes). IR
2,3-Dih yd r o-5-h yd r oxyb en zofu r a n (14a ): mp ) 106-
107 °C; Rf ) 0.51 (50% EtOAc/hexanes); IR (neat) ν 3334 br,
1
(neat) ν 3450 br, 1625, 1214, 1090, 934 cm-1; H NMR (CD3-
1
1605, 1489, 1128, 811 cm-1; H NMR (CDCl3) δ 6.70 (d, J )
OD) δ 6.38 (s, 2H), 4.53-4.41 (m, 4H), 3.81 (s, 6H), 3.14-3.05
(m, 2H), 2,81-2.72 (m, 2H) ppm; 13C NMR (CD3OD) δ 150.1,
145.0, 142.3, 130.4, 113.8, 101.5, 72.5, 56.7, 31.4 ppm. Anal.
Calcd for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.46; H,
5.59.
2.2 Hz, 1H), 6.62 (d, J ) 8.6 Hz, 1H), 6.55 (dd, J ) 8.5, 2.2,
1H), 5.09 (br s, 1H, exchanges with D2O), 4.52 (t, J ) 8.6 Hz,
2H), 3.14 (t, J ) 8.6 Hz, 2H) ppm; 13C NMR (CDCl3) δ 153.9,
149.6, 128.1, 114.1, 112.4, 109.3, 71.3, 30.1 ppm. Anal. Calcd
for C8H8O2: C, 70.58; H, 5.92. Found: C, 70.60; H, 5.94.
2,3-Dih yd r o-5-h yd r oxy-6-m e t h oxy-7-m e t h ylb e n zo-
fu r a n (14b): Rf ) 0.54 (50% EtOAc/ Hexanes). IR (neat) ν
3-Hydr oxym eth yl-4-m eth oxy-6-(2-pr open yl)ph en ol (12).
To a stirred, ice-cold suspension of 0.171 g (4.5 mmol) of LiAlH4
in THF (9.0 mL) was added a solution of 0.50 g (2.25 mmol) of
methyl benzoate 11 as a solution in THF (11.3 mL). This
mixture was stirred for 1 h, and the reaction was quenched
by dropwise addition of H2O (3 mL), MeOH (9 mL), and H2O
(3 mL). The suspension was then slowly poured into excess
ice-cold 10% HCl solution to dissolve the precipitated alumi-
num hydroxide and stirred for a period of 1 h. The organic
layer was separated, dried (Na2SO4), and filtered through a
Celite pad, and the removed solids were washed thoroughly
with Et2O. The filtrate was concentrated, and the residue was
separated using flash chromatography (90 g of SiO2, 25%
EtOAc/hexanes) to provide 0.407 g (93%) of the benzylic alcohol
as a clear liquid. This material was dissolved in diethylaniline
(3.5 mL) and rearranged according to the protocol above to
provide 0.263 g (65%) of phenol 12 and 0.087 g (21%) of the
1
3426 br, 1474, 1240, 1092, 832 cm-1; H NMR (CDCl3) δ 6.68
(s, 1H), 5.31 (s, 1H), 4.51 (t, J ) 8.6, 2H), 3.76 (s, 3H), 3.14 (t,
J ) 8.6 Hz, 2H), 2.16 (s, 3H) ppm; 13C NMR (CDCl3) δ 152.1,
144.6, 142.6, 121.3, 112.8, 108.4, 71.0, 60.9, 30.4, 9.40 ppm.
Anal. Calcd for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.55;
H, 6.67.
2,3-Dih yd r o-5-h yd r oxy-6-m eth oxyben zofu r a n (14c): Rf
) 0.46 (50% EtOAc/hexanes). IR (neat) ν 3402 br, 1502, 1461,
1320, 1157 cm-1; 1H NMR (CDCl3) δ 6.76 (s, 1H), 6.40 (s, 1H),
5.22 (br s, 1H, exchanges with D2O), 4.50 (t, J ) 8.6 Hz, 2H),
3.81 (s, 3H), 3.10 (t, J ) 8.6 Hz, 2H) ppm; 13C NMR (CDCl3) δ
153.3, 145.9, 139.5, 117.7, 110.6, 94.1, 71.5, 56.2, 29.9 ppm.
Anal. Calcd for C9H10O3: C, 65.05; H, 6.07. Found: C, 64.93;
H, 6.35.