Reactions of 3-(1-Hydroxyalkyl)phthalides with Acids
J . Org. Chem., Vol. 63, No. 8, 1998 2491
mmol) afforded the phthalide 10d (0.363 g, 76%) as a thick
2.43 (tr, J ) 7.6 Hz, 2H), 3.87 (s, 3H), 3.95 (s, 3H), 6.06 (s,
1H), 6.30 (s, 1H), 6.40 (s, 1H).
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liquid: IR ν 3417, 1747 cm-1; H NMR (90 MHz) δ 1.27 (d, J
) 6.4 Hz, 3H), 2.08 (s, 1H, exchangeable with D2O), 3.97 (s,
3H), 4.0 (s, 3H), 4.05-4.15 (m, 1H), 5.32 (d, J ) 5.14 Hz, 1H),
7.3 (bs, 2H).
Anal. Calcd for C12H14O5: C, 60.50; H, 5.92. Found: C,
60.76; H, 6.06.
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C,
67.84; H, 6.71.
8-Hyd r oxy-3-p r op ylisocou m a r in (6b). The phthalide 4b
(0.1 g, 0.423 mmol) gave the isocoumarin 6b (0.061 g, 72%) as
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a white solid: mp 38-40 °C; IR ν 3111, 1693 cm-1; H NMR
(90 MHz) δ 1.0 (tr, J ) 7.6 Hz, 3H), 1.71 (br sex, J ) 7.6 Hz,
2H), 2.47 (tr, J ) 7.6 Hz, 2H), 6.25 (s, 1H), 6.78 (d, J ) 8.8
Hz, 1H), 6.90 (d, J ) 8.8 Hz, 1H), 7.54 (tr, J ) 8.8 Hz, 1H),
10.94 (s, 1H, exchangeable with D2O).
Anal. Calcd for C12H12O3: C, 70.57; H, 5.92. Found: C,
70.30; H, 6.12.
3-(1-Hyd r oxyp en tyl)-7-m eth oxyp h th a lid e (10e). The
phthalide 9a (0.328 g, 2 mmol) and n-valeraldehyde (0.189 g,
2.2 mmol) afforded the phthalide 12 (0.430 g, 86%) as a thick
liquid: IR ν 3312, 1766 cm-1; 1H NMR (300 MHz), δ 0.89, 0.92
(2 × tr (3:1), J ) 6.9 Hz, 3H), 1.33-1.78 (m, 6H), 1.98 (bs, 1H,
exchangeable with D2O), 3.90-3.97, 4.22-4.25 (2 × m (3:1),
1H), 3.99 (s, 3H), 5.32-5.34 (m, 1H), 6.88, 6.95 (2 × d (1:3), J
) 7 Hz, 1H), 7.04, 7.10 (2 × d (1:3), J ) 7 Hz, 1H), 7.60, 7.63
(2 × tr (1:3), J ) 7 Hz, 1H).
8-Hyd r oxy-3-m eth ylisocou m a r in (7a ). The phthalide
10a (0.104 g, 0.5 mmol) provided the isocoumarin 7a (0.072 g,
82%) as a white solid: mp 99-100 °C (lit.2i mp 99-100 °C);
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IR ν 3105, 1680 cm-1; H NMR (90 MHz) δ 2.28 (s, 3H), 6.31
Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C,
67.01; H, 7.48.
(s, 1H), 6.83 (d, J ) 8.0 Hz, 1H), 6.97 (d, J ) 8.0 Hz, 1H), 7.60
(tr, J ) 8.0 Hz, 1H).
(Z)-3-Bu tylid en e-5,7-d im eth oxyp h th a lid e (5a ). A mix-
ture of the hydroxyphthalide 4a (0.266 g, 1 mmol), formic acid
(2 mL), and H3PO4 (2 mL) was stirred and heated at 80 °C for
8 h. The reaction mixture was allowed to cool to rt, poured in
ice-cold water, and then extracted two times with CH2Cl2. The
combined organic layer was washed with water and dried over
Na2SO4. The residue, obtained after removal of solvent, was
chromatographed on silica gel using 5% EtOAc/hexane as
eluent to give 3-butylidenephthalide 5a (0.203 g, 82%) as a
colorless thick liquid: IR ν 1760, 1606 cm-1; 1H NMR (90 MHz)
δ 0.84 (tr, J ) 6.3 Hz, 3H), 1.15-1.88 (m, 4H), 3.87 (s, 3H),
3.94 (s, 3H), 5.37 (tr, J ) 6.3 Hz, 1H), 6.47 (d, J ) 2.5 Hz,
2H).
Anal. Calcd for C10H8O3: C, 68.18; H, 4.58. Found: C,
68.37; H, 4.85.
6,8-Dim eth oxy-3-m eth ylisocou m a r in (8b). The phtha-
lide 10b (0.120 g, 0.5 mmol) furnished the isocoumarin 8b
(0.083 g, 76%) as a solid: mp 156 °C (lit.10k mp 154-156 °C);
IR ν 1713 cm-1 1H NMR (200 MHz) δ 2.22 (s, 3H), 3.90 (s,
;
3H), 3.98 (s, 3H), 6.14 (s, 1H), 6.35 (d, J ) 2.5 Hz, 1H), 6.47
(d, J ) 2.5 Hz, 1H).
Anal. Calcd for C12H12O4: C, 65.44; H, 5.49. Found: C,
69.19; H, 5.64.
8-Hyd r oxy-6,7-d im eth oxy-3-m eth ylisocou m a r in (7c).
The phthalide (0.134 g, 0.5 mmol) provided the isocoumarin
7c (0.083 g, 71%) as a white solid: mp 196-200 °C (lit.2j mp
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C,
67.93; H, 6.58.
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199 °C); IR ν 3111,1693 cm-1; H NMR (200 MHz) δ 2.26 (s,
3H), 3.91 (s, 3H), 3.95 (s, 3H), 6.20 (s, 1H), 6.34 (s, 1H).
Anal. Calcd for C12H12O5: C, 61.01; H, 5.12. Found: C,
61.18; H, 5.15.
(Z)-3-Bu tylid en e-7-m eth oxyp h th a lid e (5b). Following
the procedure described for 5a , but heating for 10 h, the
phthalide (4b) 0.236 g (1 mmol) provided 3-butylidenephtha-
lide 5b (0.187 g, 86%) as a colorless thick liquid (lit.12a bp 200-
203 °C (bath)/1 mm). The compound was found to be identical
(co-TLC, superposable IR, PMR) with an authentic sample of
the phthalide 5b synthesized in our laboratory.12a
Anal. Calcd for C13H14O3: C, 71.54; H, 6.47. Found: C,
71.40; H, 6.74.
8-Hyd r oxy-7-m eth oxy-3-m eth ylisocou m a r in (7f). The
phthalide 10d (0.08 g, 0.334 mmol) provided the isocoumarin
7f (0.06 g, 86%) as a white solid: mp 134 °C; IR ν 1685 cm-1
;
1H NMR (90 MHz) δ 2.24 (s, 3H), 3.93 (s, 3H), 6.21 (s, 1H),
6.41 (d, J ) 8.8 Hz, 1H), 6.97 (d, J ) 8.8 Hz, 1H), 10.75 (s,
1H, exchangeable with D2O).
Anal. Calcd for C11H10O4: C, 64.07; H, 4.89. Found: C,
64.23; H, 5.11.
(Z)-3-Bu tylid en e-7-h yd r oxy-5-m eth oxyp h th a lid e (5c).
A suspension of anhydrous AlCl3 (0.162 g, 1.2 mmol) in dry
CH2Cl2 was stirred for 20 min, and a solution of butylidene-
phthalide 5a (0.1 g, 0.4 mmol) was added. The reaction
mixture was stirred at rt for 3 h and poured into ice-cold HCl
(1:1, 15 mL). The organic layer was separated and the aqueous
layer extracted two times with CH2Cl2. The combined organic
layer was washed with water and dried over Na2SO4. The
residue, obtained after removal of solvent, was chromato-
graphed on silica gel using 2% EtOAc/hexane as eluent to give
Rea ction of th e Hyd r oxyp h th a lid es 10a -e w ith p-
TsOH in th e Absen ce of Solven t. Gen er a l P r oced u r e. A
mixture of the hydroxyphthalides 10a -e (0.5 mmol) and
p-TsOH (0.237 g, 1.25 mmol) was heated at 110 °C for varying
periods (until the starting compound disappeared as monitored
by TLC). Water was added to it and the reaction mixture
extracted three times with CH2Cl2. The residue, obtained on
usual workup, was chromatographed on silica gel using 3%
EtOAc/hexane as eluent to give the isocoumarins 7a ,c,f and
8a -c.
8-Hyd r oxy-3-m eth ylisocou m a r in (7a ) a n d 8-Meth oxy-
3-m eth ylisocou m a r in (8a ). The phthalide 10a (0.104 g) on
heating for 1.5 h provided two compounds: 8-hydroxy-3-
methylisocoumarin 7a ( 0.054 g, 62%) as a white solid, mp 99-
100 °C, identical with authentic sample (co-TLC and IR) and
the isocoumarin 8a (0.021 g, 22%) as a solid: mp 110 °C (lit.10a
mp 109.5-110.5 °C); IR ν 1734, 1693 cm-1; 1H NMR (90 MHz)
δ 2.25 (s, 3H), 3.98 (s, 3H), 6.24 (s, 1H), 6.95 (d, J ) 9.0 Hz,
2H), 7.68 (tr, J ) 9.0 Hz, 1H).
Anal. Calcd for C11H10O3: C, 69.46; H, 5.30. Found: C,
69.62; H, 5.55.
6,8-Dim eth oxy-3-m eth ylisocou m a r in (8b). The phtha-
lide 10b (0.120 g) on heating for 4 h provided the isocoumarin
8b (0.079 g, 72%) as a solid: mp 156 °C, identical with
authentic sample (co-TLC and IR).
8-H yd r oxy-6,7-d im et h oxy-3-m et h ylisocou m a r in (7c)
a n d 6,7,8-Tr im eth oxy-3-m eth ylisocou m a r in (8c). The
phthalide 10c (0.135 g) on heating for 2.5 h provided two com-
pounds: 8-hydroxy-6,8-dimethxoyisocoumarin 7c ( 0.070 g,
59%) as a solid, mp 196 °C, identical with authentic sample
(co-TLC and IR) and isocoumarin 8c (0.035 g, 28%) as a solid:
phthalide 5c (0.062 g, 65%): mp 102 °C; IR ν 3290, 1743 cm-1
;
1H NMR (90 MHz) δ 0.91 (tr, J ) 6.3 Hz, 3H), 1.16-1.85 (m,
4H), 3.84 (s, 3H), 5.28 (s, 1H, exchangeable with D2O), 5.46
(tr, J ) 6.3 Hz, 1H), 6.47 (s, 2H).
Anal. Calcd for C13H14O4: C, 66.65; H, 6.02. Found: C,
66.87; H, 6.27.
Rea ction of th e Hyd r oxyp h th a lid es 4a , 4b, a n d 10a -d
w ith p-TsOH in Tolu en e a s th e Solven t. Gen er a l P r o-
ced u r e. A solution of the hydroxyphthalides 4a , 4b , and
10a -d (0.5 mmol) in dry toluene (5 mL) containing p-TsOH
(0.237 g, 1.25 mmol) was refluxed for varying periods (until
disappearance of the starting compound as monitored by TLC).
The reaction mixture was cooled, diluted with water, and
extracted three times with CH2Cl2. The combined organic
layer was washed with water and dried over Na2SO4. The
residue, obtained after removal of solvent, was chromato-
graphed on silica gel using 5% EtOAc/hexane as eluent to give
the isocoumarins 6a ,b, 7a ,c,f, and 8b.
6,8-Dim eth oxy-3-p r op ylisocou m a r in (6a ). The phtha-
lide 4a (0.1 g, 0.375 mmol) provided the isocoumarin 6a (0.070
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g, 76%) as a white solid: mp 103-105 °C; IR ν 1720 cm-1; H
NMR (90 MHz) δ 0.94 (tr, J ) 7.6 Hz, 3H), 1.47-1.83 (m, 2H),