5580
A.N. Lowell et al. / Tetrahedron 66 (2010) 5573e5582
1.39 mmol) in DMF (7.0 mL) at ꢁ20 ꢀC was added 28 (0.112 g,
0.474 mmol) in DMF (6.0 mL). The new mixture turned yellow and
was stirred at ꢁ20 ꢀC for 2 h afterwhich the orange solution was
cooled to ꢁ45 ꢀC.23 Allyl bromide (0.55 mL, 6.46 mmol) was added
and the mixture was stirred at ꢁ45 ꢀC for 17 h afterwhich the re-
action was quenched with saturated NH4Cl (5 mL) and warmed to
rt. The mixture was further diluted with 1 N HCl (25 mL) and
extracted with EtOAc (3ꢂ25 mL). The organic layers were com-
bined, washed with saturated NH4Cl (2ꢂ25 mL) and brine
(1ꢂ25 mL), dried over Na2SO4, and concentrated to give 29 as an
amorphous yellow solid (0.123 g, 94%), which was carried on
7.33e7.37 (m, 6H), 7.34 (s,1H), 7.26e7.27 (m, 2H), 7.13 (s, 1H), 5.16 (s,
2H), 5.15 (s, 2H), 3.95 (s, 3H), 3.67 (d, J¼0.9 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 197.3,160.8,157.1,154.1,153.0,142.9,136.5,136.3,
136.2, 132.6, 129.6, 128.8, 128.80, 128.76 (2), 128.7, 125.7, 117.2, 112.0,
77.0, 75.9, 53.1, 45.7; IR (film) 3092, 3065, 3034, 3011, 2953, 2880,
2853, 2733, 1725, 1648, 1598, 1498, 1471, 1440 cmꢁ1; HRMS (ES)
calcd for C27H23O7 (MHþ) 459.1444, found 459.1462.
Sodium borohydride (0.120 g, 3.17 mmol) was combined with
EtOH (20 mL) and stirred together at rt for 1 h. This was added
dropwise to 32ald in dry THF (100 mL). The reaction was completed
by as judge TLC after about one quarter of the reducing agent had
been added. The reaction mixture was poured into 1 N HCl
(200 mL) and extracted with CH2Cl2 (1ꢂ200 mL, 2ꢂ150 mL). The
organic layers were combined, dried over Na2SO4, and concen-
trated. The resultant brown-white solid was subjected to flash
chromatography (33% acetone/hexanes) to give 32 (0.438 g, 43%) as
a white powder: mp 101e106 ꢀC; 1H NMR (500 MHz, CDCl3)
without purification: 1H NMR (500 MHz, CDCl3)
d 11.12 (s, 1H), 7.47
(s, 1H), 7.32 (d, J¼8.4 Hz, 1H), 7.06 (d, J¼8.4 Hz, 1H), 6.04e6.10 (m,
1H), 5.43e5.47 (m, 1H), 5.33e5.36 (m, 1H), 4.72e4.74 (m, 1H), 3.95
(s, 3H).
4.4. An improved synthesis of 7,8-dibenzyloxy-1-oxo-6-vinyl-
1H-isochromene-3-carboxylic acid methyl ester (2)
d 7.56e7.58 (m, 2H), 7.31e7.37 (m, 8H), 7.34 (s, 1H), 7.23 (s, 1H), 5.15
(s, 2H), 5.12 (s, 2H), 3.94 (s, 3H), 3.82 (t, J¼6.3 Hz, 2H), 2.91 (t,
4.4.1. 6-Allyl-7,8-dihydroxy-1-oxo-1H-isochromene-3-carboxylic
acid methyl ester (30)3,4. Phenol 29 (0.106 g, 0.384 mmol) and Ph2O
(12 mL) were combined and heated to reflux (heating mantle) and
stirred for 3 h. The mixture was cooled, diluted with hexanes
(w50 mL) and filtered through a plug of SiO2 (hexanes then CH2Cl2
then EtOAc). The filtrate from the EtOAc fraction was concentrated
to afford 30 (0.093 g, 88%) as a brown solid: mp: 181.5e185 ꢀC; 1H
J¼6.3 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 160.9, 157.4, 154.0,
153.2, 142.9, 142.6, 136.8, 136.3, 132.4, 129.6, 128.73, 128.66, 128.64,
128.59 (2), 125.3, 116.2, 112.3, 76.9, 75.9, 62.3, 53.0, 34.2; IR (film)
3524 (br), 3065, 3034, 2953, 2883, 1722, 1598, 1444 cmꢁ1; HRMS
(ES) calcd for C27H24O7Na (MNaþ) 461.1600, found 461.1601.
4.4.4. 7,8-Dibenzyloxy-1-oxo-6-vinyl-1H-isochromene-3-carboxylic
acid methyl ester (2). Alcohol 32 (0.438 g, 0.278 mmol) and DBU
(1.8 mL, 12.0 mmol) were combined in THF (34 mL) and cooled in
an ice bath. Methanesulfonyl chloride (0.32 mL, 4.93 mmol) in THF
(2 mL) was added dropwise to the cold solution for 0.5 h. After the
addition was completed the mixture was stirred at rt for 3 h
afterwhich the mixture was filtered through Celite (Et2O). The fil-
trate was washed with 1 N HCl (3ꢂ100 mL) and brine (2ꢂ100 mL),
dried over Na2SO4, and concentrated. The resultant yellow solid
was subjected to flash chromatography (20% acetone/hexanes,
CH2Cl2) to give 2 (0.362 g, 84%) as a white or light yellow powder:
NMR (500 MHz, CDCl3)
(s, 1H), 5.94e6.02 (m, 1H), 5.16e5.17 (m, 1H), 5.13e5.15 (m, 1H),
3.94 (s, 3H), 3.51e3.53 (m, 2H); 13C NMR (125 MHz, CDCl3)
165.1,
d 10.83 (s, 1H), 7.45 (s, 1H), 6.96 (s, 1H), 6.08
d
160.8, 147.3, 144.1, 140.9, 136.3, 134.6, 126.3, 119.8, 117.5, 114.3, 106.2,
53.0, 34.4; IR (film) 3468, 3090, 3005, 2958, 2927, 2858, 1722, 1676,
1637, 1452, 1328, 1251, 1213, 1151, 1097, 1020 cmꢁ1; HRMS (ES) calcd
for C14H13O6 (MHþ) 277.0712, found 277.0717.
4.4.2. 6-Allyl-7,8-dibenzyloxy-1-oxo-1H-isochromene-3-carboxylic
acid methyl ester (31). To 30 (0.093 g, 0.337 mmol) in acetone
(13 mL) were added K2CO3 (0.276 g, 2.00 mmol) and BnBr (0.14 mL,
1.18 mmol). The mixture was heated (60e65 ꢀC, oil bath) and stir-
red for 14 h afterwhich it was cooled, filtered through Celite (ace-
tone), and concentrated. The resultant brown solid was purified by
flash chromatography (20% acetone/hexanes) to give 31 (0.106 g,
69%) as a white powder: mp 135e137 ꢀC; 1H NMR (500 MHz, CDCl3)
mp 170.5e173 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.59e7.61 (m, 2H),
7.46 (s, 1H), 7.39 (s, 1H), 7.34e7.38 (m, 8H), 7.04 (dd, J¼11.1, 17.8 Hz,
1H), 5.92 (d, J¼17.7 Hz, 1H), 5.51 (d, J¼11.1 Hz, 1H), 5.14 (s, 2H), 5.08
(s, 2H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 161.0, 157.2, 154.8,
152.1, 142.8, 140.3, 136.6, 136.5, 132.5, 130.3, 129.6, 128.8, 128.7,
128.6 (3), 120.6, 119.9, 116.6, 112.4, 76.9, 76.3, 53.0; IR (film) 3088,
3069, 3034, 2961, 2937, 2883, 1749, 1722, 1594, 1444 cmꢁ1; HRMS
(ES) calcd for C27H22O6Na (MNaþ) 465.1314, found 465.1293.
d
7.58e7.60 (m, 2H), 7.34e7.38 (m, 8H), 7.36 (s, 1H), 7.17 (s, 1H), 5.88
(tdd, J¼6.6, 10.1, 16.9 Hz, 1H), 5.14 (dm, J¼10.4 Hz, 1H), 5.133 (s, 2H),
5.132 (s, 2H), 5.07 (dm, J¼17.0 Hz, 2H), 3.95 (s, 3H), 3.43 (dm,
J¼6.6 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d
161.0, 157.4, 154.1, 152.9,
4.5. An improved synthesis of 7-Benzyloxy-8-methoxy-1-oxo-
6-vinyl-1H-isochromene-3-carboxylic acid methyl ester (3)
144.0, 142.6, 136.9, 136.4, 135.1, 132.5, 129.6, 128.69, 128.65, 128.63,
128.61,128.5,124.6,117.8,116.0,112.3, 76.8, 75.8, 53.0, 34.7; IR (film)
3088, 3065, 3034, 2957, 2887, 1749, 1725, 1644, 1598, 1444 cmꢁ1
HRMS (ES) calcd for C28H25O6 (MHþ) 457.1651, found 457.1667.
;
4.5.1. 7-Allyloxy-8-methoxy-1-oxo-1H-isochromene-3-carboxylic
acid methyl ester (33). Phenol 29 (5.03 g,18.2 mmol), K2CO3 (25.3 g,
183 mmol), and CH3I (11.5 mL, 185 mmol) were combined in DMF
(300 mL) and stirred at rt for 20 h. The mixture was diluted with
EtOAc (500 mL) and eluted through a plug of Celite (EtOAc). The
eluant was partitioned between 1 N HCl (1 L) and EtOAc (500 mL).
The aqueous layer was washed with additional EtOAc (2ꢂ250 mL).
The combined organic layers were washed with saturated NH4Cl
(2ꢂ250 mL) and brine (500 mL), dried over Na2SO4, and concen-
trated to an oily brown solid. This residue was purified by flash
chromatography (33e50% EtOAc/hexanes, SiO2) to give the di-
methyl isocoumarin 27 (0.4 g, 8%) and 33 (3.3 g, 62%) as an off-
4.4.3. 7,8-Dibenzyloxy-6-(2-hydroxy-ethyl)-1-oxo-1H-isochromene-
3-carboxylic acid methyl ester (32). To a stirring suspension of 31
(1.0 g, 2.19 mmol) in Et2O (100 mL) was added OsO4 (0.121 g,
0.476 mmol) in acetone (20 mL).19 The mixture was stirred for
10 min. Water (100 mL) was added followed by NaIO4 (4.74 g,
22.2 mmol) in five portions over a 4 h period. Stirring was contin-
ued after the final addition for 1.5 h afterwhich the reaction was
quenched by the addition of 10% Na2S2O3 (400 mL). The mixture
was extracted with CH2Cl2 (3ꢂ300 mL), the organic layers were
combined, dried over Na2SO4, and concentrated to afford aldehyde
32ald as a light brown solid. A small amount of 32ald was purified
by flash chromatography (SiO2) for characterization purposes:
7,8-Dibenzyloxy-1-oxo-6-(2-oxo-ethyl)-1H-isochromene-3-carboxylic
acid methyl ester, a white powder: mp 158.5e160 ꢀC; 1H NMR
white solid: mp 120e122 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.34 (d,
J¼8.6 Hz, 1H), 7.33 (s, 1H), 7.26 (d, J¼8.5 Hz, 1H), 6.04 (tdd, J¼5.2,
10.6, 17.2 Hz, 1H), 5.43 (dd, J¼1.4, 17.3 Hz, 1H), 5.31 (dd, J¼1.3,
10.5 Hz,1H), 4.67 (td, J¼1.4, 5.1 Hz, 2H), 3.97 (s, 3H), 3.91 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 161.0, 157.3, 154.1, 151.9, 141.5, 132.4, 129.4,
(500 MHz, CDCl3)
d
9.58 (t, J¼1.3 Hz, 1H), 7.58e7.59 (m, 2H),
123.9, 121.5, 118.5, 117.1, 112.5, 70.3, 61.8, 52.9; IR (film) 3092, 2999,