Rearrangement and Ring Expansion with Hydrides
3-Benzyl-5-benzyloxy-3-methyl-3H-benzofuran-2-one (9).
A mixture of compound 5 (82 mg, 0.5 mmol), sodium hydroxide
(20 mg, 0.5 mmol), benzyl bromide (86 mg, 0.5 mmol), and
0.5 mL of ethanol was stirred for 2 h at room temperature.
After filtration, drying, and removal of solvent, the residue
was chromatographed on silica gel (AcOEt/Hexane ) 1/2.5) to
give product 9 as a gum (65 mg): 1H NMR (CDCl3) δ 7.39-
6.68 (m, 13H, Ar-H), 4.97 (s, 2H, C5-OCH2Ph), 3.11, 2.98
(AB, Jgem ) 15.3 Hz, 2H, C3-CH2Ph), and 1.49 (s, 3H, C3-
CH3) ppm; 13C NMR (CDCl3) δ 180.5, 155.8, 147.0, 137.1, 135.5,
132.4, 130.3, 129.0, 128.5, 128.4, 128.3, 128.1, 128.0, 115.3,
111.4, 71.2, 50.1, 45.3, and 24.3 ppm; CI-MS(CH4), m/z 345
(MH+), 317, 299, 267, and 91; HRMS m/z calcd for C23H20O3,
344.1412; found, 344.1426.
(()-5-Hydroxy-3a-methyl-2,3,3a,8a-tetrahydrofuro[2,3-
b]benzofuran (10) and (()-7-hydroxy-5-methyl-4,5-dihy-
dro-2,5-methano-1,3-benzodioxepine (14). Under a nitro-
gen atmosphere, a solution of compound 6 (1.04 g, 4.40 mmol)
in 20 mL of THF was dropwise added to lithium aluminum
hydride (0.33 g, 8.70 mmol) at room temperature. The mixture
was stirred for 1 h at room temperature, and then oxalic acid
(1.97 g, 21.90 mmol) was added and stirred for another 0.5 h
at room temperature. The mixture was filtered and concen-
trated. Resulting residues were chromatographed on silica gel
(EtOAc/Hexane ) 1/3) to give a mixture of 10 and 14 as a gum
(84.8 mg): 1H NMR (CDCl3) δ 6.75-6.60 (m, 6H, Ar-H), 5.83
(s, 1H, C8a-H of 10), 5.77 (d, J ) 1.80 Hz, 1H, C2-H of 14),
4.21-3.61 (m, 4H, C4-CH2 of 14 and C2-CH2 of 10), 2.22-
1.96 (m, 4H, C10-CH2 of 14 and C3-CH2 of 10), 1.53 (s, 3H,
C3a-CH3 of 10), and 1.50 (s, 3H, C5-CH3 of 14) ppm; GC-MS-
(CI) two peaks (1:1 ca.), m/z 193 (MH+), respectively. This was
directly used as a reactant in the following reactions without
separation.3
2-(5′-Benzyloxyphenyl-2′-hydroxy)-2-methyl-1,4-butane-
diol (11). Under a nitrogen atmosphere, lithium aluminum
hydride (184.8 mg, 4.869 mmol) was added in portions to a
solution of compound 7 (310.0 mg, 0.950 mmol) in 27 mL of
dry ether in an ice bath. The mixture was stirred for 1 h at
0 °C and at room temperature overnight. Hydrochloric acid
(1 N) was added to the reaction system up to pH 6. The formed
precipitate was removed, and solvent was also removed by
evaporation. The residue was dissolved in 30 mL of ethyl
acetate and washed with brine (2 × 20 mL). After the organic
layer was dried over sodium sulfate, filtered, and evaporated,
289 mg of crude product was afforded. This then was recrys-
tallized with chloroform to give white crystals of 11 (186 mg,
65%): mp 112.3-114.5 °C; 1H NMR (DMSO-d6) δ 9.50 (s, 1H,
ArO-H), 7.51-6.70 (m, 8H, Ar-H), 5.01 (s, 2H, CH2Ph), 4.80,
4.31(2s, 2H, C1, C4-2OH), 3.69 (d, 2H, C4-2H), 3.32-3.09
(m, 2H, C1-2H), 2.33-1.81 (m, 2H, C3-2H), and 1.31 (s, 3H,
C2-CH3) ppm; 13C NMR (DMSO-d6) δ 151.2, 150.2, 138.0,
132.5, 128.7, 128.1, 128.0, 116.6, 116.5, 112.2, 70.0, 68.5, 58.4,
42.5, 38.4, and 23.1 ppm; CI-MS(CH4), z/m: 267 (MH+ - 36),
251, 211, and 193; HRMS m/z calcd for C18H22O4, 302.1518;
found, 302.1508. Anal. Calcd for C18H24O5 (M+H2O): C, 67.48;
H, 7.55. Found: C, 67.10; H, 7.19.
116.4, 114.8, 113.7, 77.8, 70.1, 43.3, 41.4, and 25.7 ppm;
CI-MS(CH4), m/z 299 (MH+), 283, and 239; HRMS m/z calcd
for C18H18O4, 298.1205; found, 298.1211. Anal. Calcd for
C18H22O6 (M + 2H2O): C, 64.66; H, 6.63. Found: C, 64.71; H,
6.27.
3a,8a-Dihydro-5-hydroxy-3a-methyl-furo[2,3-b]benzo-
furan-2(3H)-one (13) and 4-(2′,5′-dihydroxyphenyl)-4,5-
dihydro-4-methyl-3H-furan-2-one (16). Sodium borohy-
dride (0.12 g, 3.17 mmol) was added to a solution of compound
6 (0.71 g, 3.01 mmol) in 3 mL of ethanol at 0 °C. The reaction
mixture was stirred for another 10 min at this temperature,
and then hydrogen chloride in dry ether (1 N) was added until
a pH value of 7.5-8.0 was reached. Thereafter direct chro-
matography on silica gel (EtOAc/Hexane ) 1/3) afforded
product 13 as a gum (0.12 g): 1H NMR (CDCl3) δ 6.72-6.56
(m, 3H, Ar-H), 6.03 (s, 1H, C8a-H), 2.90, 2.72 (AB, Jgem )
18.0 Hz, 2H, C3-H), and 1.49 (s, 3H, C3a-CH3) ppm; 13C NMR
(CDCl3) δ 173.9, 152.2, 150.7, 132.8, 116.9, 113.6, 111.9, 110.7,
50.7, 41.9, and 24.2 ppm; CI-MS(CH4), m/z 207 (MH+), 189,
177, 161, and 149; HRMS m/z calcd for C11H10O4, 206.0579;
found, 206.0582. Other white crystals of 16 (0.30 g, 48%): mp
1
182.5-184.0 °C; H NMR (CD3OD) δ 6.54-6.40 (m. 3H, Ar-
H), 4.79 (s, 2H, Ar-OH), 4.52, 4.38 (AB, Jgem ) 5.40 Hz, 2H,
C5-H), 2.97, 2.57 (AB, Jgem ) 18.1 Hz, 2H, C3-H), and 1.39
(s, 3H, C4a-H) ppm; 13C NMR (CD3OD) δ 180.0, 151.7, 149.6,
132.7, 118.0, 115.8, 115.1, 80.5, 44.8, 43.1, and 26.4 ppm;
CI-MS(CH4), m/z 209 (MH+), 191, 177, 164, and 149; HRMS
m/z calcd for C11H13O4, 209.0814; found, 209.0817.
5-Benzyloxy-3-carboxymethylene-3-methyl-2,3-dihy-
drobenzofuran (17), 7-Benzyloxy-5-methyl-4,5-dihydro-
2,5-methano-1,3-benzodioxepine (23), 6-Benzyloxy-3,4-
dihydro-4-ethoxycarbonyl-4-methyl-2H-1-benzopyran-2-
one (24), and 5-Benzyloxy-3-ethoxycarbonylmethylene-
3-methyl-3H-benzofuran-2-one (25). Sodium borohydride
(71.4 mg, 1.887 mmol) was added to a solution of compound 7
(405.0 mg, 1.241 mmol) in 24 mL of ethanol at room temper-
ature and was stirred for 17 h at the same temperature. Oxalic
acid (428.0 mg, 4.753 mmol) was added to this reaction system
and then continuously reacted for 0.5 h at room temperature.
Thereafter, direct chromatography on silica gel (EtOH/
CH2Cl2 ) 1/155) gave white crystals of 17 (228 mg, 62%): mp
1
130.0-132.5 °C; H NMR (CDCl3) δ 10.3 (s, br, 1H, COOH),
7.39-6.60 (m, 8H, Ar-H), 4.91 (s, 2H, CH2Ph), 4.51, 4.22 (AB,
Jgem ) 9.0 Hz, 2H, C2-H), 2.63 (s, 2H, C3-CH2COOH), and
1.38 (s, 3H, C3-CH3) ppm; 13C NMR (CDCl3) δ 175.6, 153.9,
153.7, 137.6, 135.4, 128.9, 128.3, 128.0, 115.1, 110.8, 110.3,
82.9, 71.5, 44.4, 43.9, and 25.1 ppm; CI-MS(CH4), m/z 297
(M+ - 1), 281, 269, 251, 235, 219, 207, 177, 166, 153, 136, 121,
112, 100, 91, and 55; HRMS m/z calcd for C18H18O4, 298.1205;
found, 298.1210. Anal. Calcd for C18H20.6O5.3 (M + 1.3H2O):
C, 67.19; H, 6.45. Found: C, 66.88; H, 5.68. The second product
23 (21 mg, 6%): 1H NMR (CDCl3) δ 7.46-6.71 (m, 8H, Ar-
H), 5.73 (d, J ) 1.80 Hz, 1H, C2-H), 5.01 (s, 2H, CH2Ph), 4.18,
3.76 (AB, Jgem ) 6.3 Hz, 2H, C4-H), 2.21, 2.00 (AB, Jgem )
14.9 Hz, 2H, C10-H), and 1.51 (s, 3H, C5-CH3) ppm; 13C NMR
(CDCl3) δ 152.9, 145.7, 137.2, 132.7, 128.6, 128.0, 127.6, 116.6,
113.7, 111.3, 100.4, 84.4, 70.8, 39.9, 39.7, and 16.9 ppm;
CI-MS(CH4), m/z: 282 (M+), 265, 239, 205, 191, 175, 161, 149,
119, 100, and 91; HRMS m/z calcd for C18H19O3, 283.1334;
found, 283.1327. The third product 24 (25 mg, 6%): 1H NMR
(CDCl3) δ 7.42-6.82 (m, 8H, Ar-H), 5.06 (s, 2H, CH2Ph), 4.12
(q, J ) 7.2 Hz, 2H, OCH2CH3), 3.11, 2.60 (AB, Jgem )
16.2 Hz, 2H, C3-H), 1.58 (s, 3H, C4-CH3), and 1.21 (t, J )
7.2 Hz, 3H, CH3CH2O) ppm; 13C NMR (CDCl3) δ 173.1, 166.0,
156.0, 145.4, 136.9, 129.0, 128.6, 127.9, 118.6, 115.7, 113.0,
110.0, 71.0, 62.5, 44.6, 39.6, 23.3, and 14.2 ppm; CI-MS(CH4)
m/z 341 (MH+), 313, 295, 281, 267, 253, and 91; HRMS m/z
calcd for C20H21O5, 341.1389; found, 341.1402. Anal. Calcd for
C20H20O5: C, 70.57; H, 5.92. Found: C, 70.37; H, 6.20. The
fourth product 25 (90 mg, 21%): 1H NMR (CDCl3) δ 7.47-
6.76 (m, 8H, Ar-H), 5.02 (s, 2H, CH2Ph), 3.94 (q, J ) 8.1 Hz,
2H, OCH2CH3), 3.10, 2.85 (AB, Jgem ) 18.0 Hz, 2H, C3-
4-(5′-Benzyloxyphenyl-2′-hydroxy)-4,5-dihydro-4-meth-
yl-3H-furan-2-one (12). Under a nitrogen atmosphere, lithium
borohydride (4.56 mg, 0.209 mmol) was added to a solution of
compound 7 (68.0 mg, 0.208 mmol) in 4 mL of dry ether at
0 °C. The mixture was reacted for 0.5 h. Placed in an ice bath,
2.5 g of ice was added to the above reaction system, which
was stirred for 5 min. After filtering, the residue was extracted
with ethyl acetate (2 × 10 mL). The combined organic layer
was dried over sodium sulfate and then evaporated to remove
solvents. The residue was recrystallized with AcOEt/
CH2Cl2(1/6) to give white crystals of 12 (40.3 mg, 65%): mp
1
162.0-164.0 °C; H NMR (DMSO-d6) δ 9.41 (s, 1H, ArO-H),
7.65-6.84 (m, 8H, Ar-H), 5.13 (s, 2H, CH2Ph), 4.68, 4.52 (AB,
Jgem ) 11.7 Hz, 2H, C5-H), 3.17, 2.80 (AB, Jgem ) 18.9 Hz,
2H, C3-H), and 1.51 (s, 3H, C4-CH3) ppm; 13C NMR (DMSO-
d6) δ 176.7, 151.6, 149.1, 137.8, 131.5, 128.7, 128.2, 128.1,
J. Org. Chem, Vol. 70, No. 16, 2005 6175