9312 J . Org. Chem., Vol. 62, No. 26, 1997
Bunnell et al.
stirred rapidly and heated to 100 °C for 1 h. The mixture was
cooled to room temperature, brought to pH ) 12 using aqueous
NaOH, and extracted with 3 × 50 mL of CH2Cl2. These CH2Cl2
layers were discarded. The strongly basic aqueous layer was
neutralized to pH ) 7 using 4 M HCl and extracted with 3 ×
50 mL of CH2Cl2. The combined organic layers were dried
(MgSO4), filtered, and concentrated with a rotary evaporator
to give 271 mg of a crude product. Purification of the crude
material by flash chromatography (silica gel, 95:5 CH2Cl2-
CH3OH) afforded 228 mg (60%) of 16a as a white crystalline
with BMS under conditions identical with those described
above gave 220 mg (56%) of 17b and 114 mg (26%) of ester
18b as colorless oils.
17b: 1H NMR δ 9.17 (s, 1 H), 6.89 (s, 1 H), 4.09 (s, 3 H),
4.01 (s, 3 H), 3.96 (s, 3 H), 3.86-3.75 (m, 2 H), 3.28-3.18 (m,
1 H), 2.99 (br t, J ) 6 Hz, 2 H), 2.10-1.70 (m, 6 H); 13C NMR
δ 157.0, 152.0, 149.2, 143.3, 140.4, 133.7, 123.9, 118.0, 96.8,
62.2, 61.9, 61.3, 56.1, 40.5, 38.9, 31.1, 25.6, 20.6; LSIMS-
HRMS Calcd for C18H24NO4 (M + H): 318.1705. Found:
318.1700. Anal. Calcd for C18H23NO4 (0.5 mol H2O): C, 66.24;
H, 7.41; N, 4.29. Found: 66.39; H, 7.24; N, 4.46.
1
solid: mp 152-153 °C; H NMR δ 8.79 (s, 1 H), 7.06 (s, 1 H),
18b: 1H NMR δ 9.21 (s, 1 H), 6.89 (s, 1 H), 4.25-4.13 (m, 2
H), 4.09 (s, 3 H), 4.01 (s, 3 H), 3.96 (s, 3 H), 3.62-3.49 (m, 1
H), 3.20 (dd, J ) 15.5, 4.4 Hz, 1 H), 2.98 (br t, J ) 5.9 Hz, 1
H), 2.53 (dd, J ) 15.5, 9.7 Hz, 1 H), 2.19-1.68 (m, 4 H), 1.28
(t, J ) 7.1 Hz, 3 H); 13C NMR δ 173.3, 156.7, 151.2, 149.2,
144.2, 140.4, 133.3, 118.1, 107.1, 96.9, 61.9, 61.3, 60.2, 56.0,
40.1, 37.9, 28.2, 25.5, 20.0, 14.3.
4.03 (s, 3 H), 4.00 (s, 3 H), 3.94 (s, 3 H), 3.58 (br dt, J ) 18.3,
4 Hz, 1 H), 3.5-3.37 (m, 1 H), 3.32-3.18 (m, 1 H), 2.85 (dd, J
) 15.6, 10.0 Hz, 1 H), 2.68 (dd, J ) 15.6, 1.2 Hz, 1 H), 2.21-
2.12 (m, 1 H), 2.10-2.02 (m, 1 H), 1.81-1.54 (m, 2 H); 13C NMR
δ 176.9, 155.9, 152.2, 150.9, 149.5, 147.8, 130.0, 129.4, 127.1,
105.2, 63.5, 63.2, 58.2, 46.0, 39.4, 33.4, 30.1, 24.4; LSIMS m/z
332 (M + H, 100%), 314 (5%), 286 (5%), 272 (5%). Anal. Calcd
for C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C, 65.11;
H, 6.38; N, 4.38.
(7,8,9-Tr im eth oxy-1,2,3,4-tetr a h yd r op h en a n th r id in -4-
yl)a cetic Acid (16b). Compound 14b (1.00 g, 2.3 mmol) was
allowed to react in 100 mL of aqueous 6 M HCl at 23 °C under
a nitrogen atmosphere for 36 h. The reaction mixture was
then exposed to air and heated to 110 °C for 1.5 h. The
reaction mixture was cooled to room temperature, adjusted to
pH ) 7 with aqueous 3 M NaOH, and extracted with CH2Cl2.
The combined organic layers were dried (MgSO4), filtered, and
concentrated to give 600 mg of a crude residue. The crude
material was purified using flash chromatography (silica gel,
95:5 CH2Cl2-CH3OH) to afford 300 mg (40%) of 16b as a white
crystalline solid: mp 139-141 °C; 1H NMR δ 9.16 (s, 1 H),
6.91 (s, 1 H), 4.13 (s, 3 H), 4.05 (s, 3 H), 3.98 (s, 3 H), 3.50-
3.39 (m, 1 H), 3.16-3.05 (m, 1 H), 2.99-2.76 (m, 1 H), 2.84
(dd, J ) 15, 10 Hz, 1 H), 2.67 (dd, J ) 15, 1 Hz, 1 H), 2.22-
2.10 (m, 2 H), 1.93-1.78 (m, 1 H), 1.67-1.55 (m, 1 H); 13C NMR
δ 174.9, 158.6, 149.7, 149.3, 141.8, 140.9, 134.3, 125.3, 118.2,
96.9, 61.9, 61.4, 56.2, 43.5, 36.7, 31.7, 25.4, 21.7; EI-MS m/z
331 (M, 35%), 287 (65%), 286 (100%), 272 (30%), 258 (10%),
256 (15%), 242 (20%), 228 (20%). Anal. Calcd for C18H21NO5:
C, 65.24; H, 6.39; N, 4.23. Found: C, 65.15; H, 6.32; N, 4.36.
2-(8,9,10-Tr im eth oxy-1,2,3,4-tetr a h yd r op h en a n th r id in -
4-yl)eth a n ol (17a ). To a solution of 16a (200 mg, 0.6 mmol)
in 10 mL of THF at 23 °C was added 0.32 mL (0.64 mmol) of
neat BMS over 1 h. After 4 h the solvent was removed with
a rotary evaporator, and the residue was dissolved in 15 mL
of 2 M ethanolic HCl. The reaction mixture was allowed to
reflux for 45 min and concentrated to a solid residue under
vacuum. The residue was dissolved in ca. 5 mL of water,
adjusted to pH ) 12 with NaOH, and extracted with CH2Cl2
to give 190 mg of a crude product. The crude material was
purified using flash chromatography (silica gel, 98:2 CH2Cl2-
CH3OH) to give 105 mg (55%) of 17a and 64 mg (30%) of ester
18a as colorless oils.
17a : 1H NMR δ 8.79 (s, 1 H), 7.00 (s, 1 H), 4.00 (s, 3 H),
3.98 (s, 3 H), 3.92 (s, 3 H), 3.88-3.72 (m, 2 H), 3.39 (br t, J )
6 Hz, 2 H), 3.27-3.17 (m, 1 H), 2.09-1.64 (m, 6 H); 13C NMR
δ 153.3, 151.3, 150.5, 147.7, 146.7, 127.6, 126.2, 125.4, 103.3,
62.6, 61.7, 61.4, 56.3, 41.2, 39.7, 31.0, 28.4, 21.5. EI-MS m/z
317 (M, 7%), 286 (7%), 273 (100%), 258 (30%), 242 (12%), 228
(5%). An analytically pure derivative was obtained by recrys-
tallization of the picrate salt of 17a from abs ethanol: mp
(picrate) 123-124 °C. Anal. Calcd for C24H26N4O11: C, 52.75;
H, 4.80; N, 10.25. Found: C, 52.78; H, 4.78; N, 10.20.
1a (Br -). Meth od A.14 Compound 17a (58 mg, 0.18 mmol)
was dissolved in 10 mL of benzene. To this solution was added
0.2 mL of PBr3 in 2 mL of 1:1 ether-hexane, and the reaction
mixture was allowed to reflux under a nitrogen atmosphere
for 2.5 h. Methanol (2 mL) was added, and the reaction
mixture was concentrated with a rotary evaporator. The crude
residue was purified by flash chromatography (silica gel, 95:5
CH2Cl2-CH3OH) to give 30 mg (44%) of 1a (Br-): 1H NMR δ
10.45 (s, 1 H), 7.89 (s, 1 H), 5.34 (br dd, J ) 13.3, 8.3 Hz, 1 H),
4.88 (ddd, J ) 13.3, 13.3, 6.3 Hz, 1 H), 4.09 (s, 3 H), 4.07 (s, 3
H), 3.97 (s, 3 H), 3.73 (br dd, J ) 18.7, 6.3 Hz, 1 H), 3.51-3.36
(m, 1 H), 3.27-3.12 (m, 1 H), 2.74 (br ddd, J ) 12.5, 6.3, 6.3
Hz, 1 H), 2.44-2.26 (m, 2 H), 2.10 (dddd, J ) 12.2, 12.2, 12.2,
8.3 Hz, 1 H), 2.02-1.82 (m, 1 H), 1.45 (dddd, J ) 11.8, 11.8,
11.8, 2.8 Hz, 1 H); 13C NMR δ 155.5, 150.6, 149.2, 144.1, 142.5,
129.0, 128.9, 125.4, 106.6, 61.7, 61.4, 57.3, 57.0, 41.0, 31.8, 26.6,
26.1, 22.9. See the Supporting Information for proton assign-
ments and detailed results of a 1H NMR solvent-effect study
using three solvents. EI-MS m/ s 300 (M, 2%), 286 (24%), 285
(100%),284 (19%), 271 (22%), 270 (92%), 267 (32%), 266 (52%),
256 (60%), 254 (40%), 242 (86%), 239 (21%), 239 (8%), 238
(48%), 228 (8%), 227 (16%), 226 (15%), 225 (8%), 212 (12%),
199 (33%), 183 (8%), 171 (30%), 170 (12%), 167 (9%), 154 (12%),
143 (15%), 142 (20%), 128 (8%), 127 (6%), 115 (14%), 102 (4%),
89 (4%), 77 (5%); LSIMS-HRMS Calcd for C18H22NO3:
300.1600. Found: 300.1607. Meth od B. Compound 17a (39
mg, 0.12 mmol) was dissolved in 10 mL of benzene. To this
solution was added 33 mg (0.12 mmol) of PBr3 in 1 mL of 1:1
ether-hexane, and the reaction mixture was allowed to reflux
for 10 min. The reaction mixture was concentrated under
vacuum, and the residue was purified by flash chromatography
(silica gel, 94:6 CH2Cl2-CH3OH) to afford 37 mg (76%) of 1a
(Br-).
1a (Cl-). To a solution of compound 17a (120 mg, 0.38
mmol) in 10 mL of benzene was added 52 mg (0.38 mmol) of
PCl3 in 1 mL of benzene. The reaction mixture was allowed
to reflux for 20 min under a nitrogen atmosphere, 2 mL of
methanol was added, and the mixture was concentrated with
a rotary evaporator. The crude residue was purified by flash
chrmatography (silica gel, 92:8 CH2Cl2-CH3OH) to give 127
mg (87%) of 1a (Cl-): darkens 92 °C; mp 92.5-93 °C; See the
Supporting Information for proton assignments and detailed
1
results of a H NMR solvent-effect study using three solvents;
EI-MS m/z 300 (M, 2%), 286 (20%), 285 (100%), 284 (20%),
271 (16%), 270 (86%), 267 (29%), 266 (46%), 256 (60%), 254
(36%), 242 (60%), 239 (16%), 238 (36%), 228 (4%), 227 (13%),
226 (10%), 225 (4%), 212 (9%), 199 (20%), 183 (6%), 171 (20%),
170 (10%), 167 (7%), 154 (6%), 143 (11%), 142 (10%), 128 (4%),
127 (6%), 115 (10%), 102 (2%), 89 (6%), 77 (6%).
18a : 1H NMR δ 8.83 (s, 1 H), 7.00 (s, 1 H), 4.27-4.14 (m,
2H), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.92 (s, 3 H), 3.61-3.49 (m, 1
H), 3.43-3.34 (m, 1 H), 3.18 (dd, J ) 15.3, 4.3 Hz, 1 H), 2.52
(dd, J ) 15.3, 9.8 Hz, 1 H), 2.14-1.67 (m, 4 H), 1.28 (t, J )
7.2 Hz, 3 H); 13C NMR δ 173.4, 152.8, 150.2, 150.1, 148.4,
146.0, 126.7, 125.4, 125.2, 102.8, 61.3, 61.0, 60.2, 55.9, 40.7,
38.6, 27.88, 27.86, 20.7, 14.3; EI-MS m/z 359 (M, 64%), 344
(6%), 314 (11%), 298 (4%), 286 (100%); EI-HRMS Calcd for
1b (Br -). To a solution of 17b (14.0 mg, 0.044 mmol) in 4
mL of benzene was added 1 drop of PBr3. The solution was
allowed to reflux for 20 min under a nitrogen atmosphere,
cooled to room temperature, diluted with 1 mL of methanol,
and concentrated with a rotary evaporator. The crude product
was purified by flash chromatography (silica gel, 96:4 CH2Cl2-
CH3OH) to give 10.0 mg (60%) of 1b (Br-): 1H NMR δ 9.93 (s,
1 H), 6.94 (s, 1 H), 5.37 (br dd, J ) 12.5, 8.3 Hz, 1 H), 5.07
(ddd, J ) 12.5, 12.5, 6.3 Hz, 1 H), 4.27 (s, 3 H), 4.13 (s, 3 H),
C
20H25NO5: 359.1733. Found: 359.1732.
2-(7,8,9-Tr im eth oxy-1,2,3,4-tetr a h yd r op h en a n th r id in -
4-yl)eth a n ol (17b). Reduction of 411 mg (1.24 mmol) of 16b