1962 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 10
Schultz et al.
as a light brown solid: 1H NMR (CDCl3) δ 10.56 (bs, exchange-
able with D2O, COOH), 7.81 (d, 1 H, J ) 8.5 Hz), 7.29 (d, 1 H,
J ) 8.5 Hz), 6.94 (d, 1 H, J ) 8.0 Hz), 6.76 (d, 1 H, J ) 2.5
Hz), 6.68 (dd, 1 H, J ) 2.5, 8.0 Hz), 6.21 (d, exchangeable with
D2O, NH), 3.76 (s, 3 H), ∼3.7 (m, 1 H), 3.10 (d, 1 H, J ) 17.5
Hz), 2.86 (d, 1 H, J ) 17.5 Hz), 2.38 (s, 3 H), 1.94 (d, 1 H, J )
13.5 Hz), 1.80 (d, 1 H, J ) 13.5 Hz), 1.63 (m, 1 H), 1.48 (d, 1
H, J ) 12.5 Hz), 1.35 (s, 3 H), 1.13-1.25 (m, 2 H); 13C (CDCl3)
δ 179.7, 158.1, 143.8, 143.3, 137.5, 129.6, 128.4, 127.1, 126.5,
111.6, 110.0, 55.8, 55.1, 45.6, 37.0, 35.2, 34.5, 34.4, 27.7, 25.0,
21.5; CIMS, m/ z (relative intensity) 430 (M+ + 1, 68), 276 (73),
157 (100).
for C16H24NO2 (M + H)+ 262.1807, found 262.1803; (-)-3a
[R]30 -64° (c 1.0, EtOH). Anal. (C16H23NO2‚1/2H2O) C, H.
D
(5S ,8S ,9S )-8-Am in o -3-h y d r o x y -5,9-m e t h a n o -9-(h y -
dr oxym eth yl)-5-m eth ylben zocycloocten e [(+)-3b]: 1H NMR
(CDCl3) δ 6.91 (d, 1 H, J ) 8.1 Hz), 6.72 (d, 1 H, J ) 2.6 Hz),
6.60 (dd, 1 H, J ) 2.6, 8.2 Hz), 3.69 (d, 1 H, J ) 11.7 Hz), 3.26
(d, 1 H, J ) 11.5 Hz), 3.03 (bs, 1 H), 2.36 (s, 2 H), 2.06 (d, 1 H,
J ) 13.6 Hz), 1.45 (s, 3 H), 1.3-1.5 (m, 9 H).
(5S,8S,9S)-3-Hyd r oxy-5,9-m eth a n o-9-(h yd r oxym eth yl)-
5-m eth yl-8-(N,N-d im eth yla m in o)ben zocycloocten e [(+)-
3c]: 1H NMR (CDCl3) δ 6.82 (d, 1 H, J ) 8.1 Hz), 6.77 (d, 1 H,
J ) 2.3 Hz), ∼6.7 (b, exchangeable with D2O, 1 H), 6.63 (dd,
1 H, J ) 2.5, 8.2 Hz), 3.82 (d, 1 H, J ) 11.1 Hz), 3.50 (d, 1 H,
J ) 11.0 Hz), 2.70 (d, 1 H, J ) 5.7 Hz), 2.43 (s, 3 H), 2.40 (s,
2 H), 2.09 (d, 1 H, J ) ∼14 Hz), 1.36 (s, 3 H), 1.2-1.8 (m, 6
H); 13C (CDCl3) δ 154.6, 144.9, 128.5, 127.4, 113.3, 111.2, 73.9,
67.8, 44.5, 41.3, 38.7, 38.1, 37.9, 34.8, 28.8, 18.2; IR (film)
∼3200 (broad) cm-1; CIMS, m/ z (relative intensity) 276 (M+
+ 1, 100); [R]24D +83° (c 2.2, EtOH); (-)-3c: [R]23D -80° (c 2.0,
EtOH). Anal. (C17H25NO2‚HCl) C, H.
(5S,8S,9S)-5,9-Meth a n o-3-m eth oxy-9-(m eth oxym eth yl)-
5-m et h yl-8-(N-t osyla m in o)b en zocyclooct en e [(+)-10].
Lithium aluminum hydride (0.210 g, 5.53 mmol) was added
to a solution of (+)-9 (1.509 g, 3.52 mmol) in 45 mL of THF at
4 °C. The solution was refluxed overnight, brine was then
added at 4 °C, and solid material was filtered. The filtrate
was extracted with CH2Cl2, and the organic layers were dried
over Na2SO4 and concentrated to give the alcohol as a white
foam (1.353 g, 93%). To a solution of the alcohol (1.108 g, 2.67
mmol) in 20 mL of THF was added sodium hydride (0.285 g,
11.9 mmol). The mixture was stirred at room temperature
for 1 h, 170 µL of methyl iodide (2.73 mmol) was then
introduced, and stirring was continued for 1 h. Additional
addition of methyl iodide was added (20 µL, total 0.19 mL,
3.05 mmol). After 4 h, excess NaH was quenched with water
cooled to 4 °C, and the resulting solution was acidified with
concentrated HCl and extracted with CH2Cl2. The combined
organic layers were dried over Na2SO4 and concentrated.
Flash chromatography on silica gel (Et2O-hexane, 3:7) pro-
vided (+)-10 (0.974 g, 85%): mp 181.5-182.5 °C; 1H NMR
(CDCl3) δ 7.79 (d, 2 H, J ) 8.3 Hz), 7.30 (d, 2 H, J ) 8.3 Hz),
6.90 (d, 1 H, J ) 8.6 Hz), 6.76 (d, 1 H, J ) 2.7 Hz), 6.66 (dd,
1 H, J ) 2.7, 8.3 Hz), 6.06 (m, 1 H), 3.75 (s, 3 H), 3.25 (m, 1
H), 3.19 (s, 3 H), 3.16 (d, 1 H, J ) 9.0 Hz), 3.01 (d, 1 H, J )
9.0 Hz), 2.74 (d, 1 H, J ) 17.8 Hz), 2.44 (d, 1 H, J ) 17.8 Hz),
2.42 (s, 3 H), 1.72-1.65 (m, 1 H), 1.61 (d, 1 H, J ) 13.2 Hz),
1.47 (d, 1 H, J ) 13.4 Hz), 1.39 (d, 1 H, J ) 13.2 Hz), 1.33 (s,
3 H), 1.21-1.15 (m, 2 H); 13C NMR (CDCl3) δ 157.8, 144.6,
143.0, 137.7, 129.5, 128.2, 127.8, 127.1, 111.2, 109.9, 81.2, 59.1,
57.1, 55.1, 37.5, 37.4, 36.7, 34.9, 34.4, 27.9, 25.4, 21.4; IR (CH2-
Cl2) 3236, 2934, 1610, 1496, 1333, 1160 cm-1; HRMS calcd for
C24H32NO4S (M + H)+ 430.2052, found 430.2058.
(5S,8S,9S)-8-Am in o-3-h yd r oxy-5,9-m et h a n o-9-(m et h -
oxym et h yl)-5-m et h ylb en zocyclooct en e [(+)-3a ]. To a
stirred solution of (+)-10 (0.312 g, 0.727 mmol) and ethanethiol
(0.30 mL, 4.1 mmol) in 4 mL of DMF at 4 °C was added sodium
hydride (0.145 g, 6.04 mmol). The mixture was refluxed
overnight. A few drops of concentrated HCl was added to the
reaction mixture cooled (4 °C), and DMF was evaporated under
reduced pressure. The residue was partitioned between CH2-
Cl2 and water. The organic layers were dried (Na2SO4),
concentrated, and chromatographed on silica gel to give the
phenol as a yellow foam (0.271 g, 90%). To a solution of the
phenol (0.271 g, 0.653 mmol) in 6 mL of THF and ∼30 mL of
NH3 at -78 °C was added small pieces of sodium until a dark
blue coloration persisted. The solution was stirred at -78 °C
for 30 min then quenched with solid NH4Cl. NH3 was allowed
to evaporate and the remaining mixture was diluted with brine
and extracted with CH2Cl2. Chromatography on two alumina
preparative TLC plates (1.5 mm, EtOAc-hexane, 1:1). The
band at the baseline was removed and extracted with 30%
MeOH in CH2Cl2. After removal of the solvents under reduced
pressure, the residue was dissolved in CH2Cl2 and washed with
water. Evaporation of solvent afforded (+)-3a as a yellow foam
(0.127 g, 75%): 1H NMR (CDCl3) δ 6.92 (d, 1 H, J ) 8.0 Hz),
6.73 (d, 1 H, J ) 2.5 Hz), 6.60 (dd, 1 H, J ) 2.7, 8.3 Hz), 3.43
(d, 1 H, J ) 8.8 Hz), 3.37 (s, 3 H), 3.10 (d, 1 H, J ) 8.8 Hz),
3.06 (m, 1 H), 2.89 (d, 1 H, J ) 17.6 Hz), 2.65 (d, 1 H, J ) 17.8
Hz), 1.69 (dt, 1 H, J ) 4.4, 13.2 Hz), 1.58 (d, 1 H, J ) 12.9
Hz), 1.42-1.30 (m, 2 H), 1.33 (s, 3 H), 1.28 (d, 1 H, J ) 12.7
Hz), 1.22-1.19 (m, 1 H); 13C NMR (CDCl3) δ 154.8, 144.3,
128.4, 127.5, 113.5, 111.3, 81.9, 59.3, 52.4, 38.8, 37.8, 36.2, 35.0,
34.6, 28.1, 27.1; IR (CH2Cl2) 3584, 2924 (overlap with a broad
peak), 1609, 1110 cm-1; [R]27D +62° (c 1.0, EtOH); HRMS calcd
(5S,8S,9S)-3-Hyd r oxy-5,9-m eth a n o-9-(h yd r oxym eth yl)-
5-m eth yl-8-(N-m eth yla m in o)ben zocycloocten e [(+)-3d ]:
1H NMR (CDCl3) δ 6.86 (d, 1 H, J ) 8.2 Hz), 6.76 (d, 1 H, J )
2.5 Hz), 6.23 (dd, 1 H, J ) 2.6, 8.2 Hz), ∼4.4 (bs, exchangeable
with D2O, 3 H), 3.83 (d, 1 H, J ) 10.7 Hz), 3.39 (d, 1 H, J )
10.7 Hz), 2.56 (bs, 1 H), 2.43 (s, NCH3), 2.34 (s, 2 H), 1.95 (d,
1 H, J ) 13.5 Hz), 1.35 (s, 3 H), 1.1-1.6 (m, 5 H); IR (film)
3200 (broad) cm-1; CIMS, m/ z (relative intensity) 262 (M++1,
100); [R]25 +63° (c 1.5, CHCl3); (-)-3d : [R]28 -66° (c 1.4,
D
D
CHCl3).
(5S,8S,9S)-3-Hyd r oxy-5,9-m eth a n o-9-(m eth oxym eth yl)-
5-m e t h y l-8-(N ,N -d im e t h y la m in o )b e n zo c y c lo o c t e n e
[(+)-3e]: 1H NMR (CDCl3) δ 6.88 (d, 1 H, J ) 8.1 Hz), 6.74 (d,
1 H, J ) 2.0 Hz), 6.60 (dd, 1 H, J ) 2.2, 8.1 Hz), ∼ 5.65 (b,
exchangeable with D2O, OH), 3.58 (d, 1 H, J ) 8.9 Hz), 3.36
(s, 3 H), 3.22 (d, 1 H, J ) 8.8 Hz), 3.06 (d, 1 H, J ) 17.6 Hz),
2.93 (d, 1 H, J ) 12.8 Hz), 2.37 (s, 6 H), 2.34-2.53 (m, 1 H),
1.31 (s, 3 H), 1.10-1.79 (m, 6 H); 13C (CDCl3) δ 154.1, 144.6,
128.8, 128.5, 113.2, 111.1, 80.7, 64.2, 59.0, 58.3, 44.7, 40.3, 39.1,
38.9, 38.6, 34.4, 28.6, 18.6, 18.2; IR (film) 3310 (b), 3000-2800,
2760, 1600, 1450, 1230, 1100 cm-1; CIMS, m/ z (relative
intensity) 290 (M+ + 1, 100), 258 (94).
(5S,8S,9R)-3-Hydr oxy-5,9-m eth an o-5,9-dim eth yl-8-(N,N-
dim eth ylam in o)ben zocycloocten e [(+)-3f]: 1H NMR (CDCl3)
δ 6.87 (d, 1 H, J ) 8.3 Hz), 6.73 (d, 1 H, J ) 2.7 Hz), 6.59 (dd,
1 H, J ) 2.7, 8.2 Hz), ∼5.90 (b, exchangeable with D2O, OH),
2.75 (d, 1 H, J ) 17.5 Hz), 2.50 (dd, 1 H, J ) 1.7, 17.1 Hz),
2.36 (s, 6 H), 2.30 (m, 1 H), 1.33 (s, 3 H), 1.14 (s, 3 H), 0.95-
1.84 (m, 6 H); 13C (CDCl3) δ 153.8, 144.8, 129.7, 128.3, 112.9,
111.2, 66.9, 46.6, 44.5, 44.2, 39.1, 35.4, 28.9, 28.6, 18.7, 18.4;
IR (film) 3300 (b), 3000-2800 cm-1; CIMS, m/ z (relative
intensity) 260 (M+ + 1, 100); [R]30 +110° (c 0.30, EtOH); (-)-
D
3f: [R]32 -66° (c 0.47, EtOH).
D
(5S,8S,9R)-3-Hyd r oxy-5,9-m eth a n o-N,5-d im eth yla zeti-
d in o[2,3-i]ben zocycloocten e [(+)-3g]: 1H NMR (CDCl3) δ
∼8.9 (bs, exchangeable with D2O, OH), 6.86 (d, 1 H, J ) 8.1
Hz), 6.72 (d, 1 H, J ) 2.0 Hz), 6.58 (dd, 1 H, J ) 2.2, 8.1 Hz),
3.31 (d, 1 H, J ) 6.5 Hz), 2.49-2.85 (m, 4 H), 2.33 (s, NCH3),
2.05 (dfs, 1 H, J ) 12.4 Hz), 1.26 (s, 3 H), 1.11-1.73 (m, 5 H);
13C (CDCl3) δ 155.3, 144.8, 130.0, 127.1, 113.5, 113.2, 72.3,
64.7, 44.2, 43.0, 41.0, 37.7, 36.6, 35.8, 29.4, 22.9; IR (film) 3300
(b), 3100-2750 (b) cm-1; CIMS, m/ z (relative intensity) 244
(M+ + 1, 100).
3,6-Dim eth ylqu in a zolin e-2,4-d ion e (12). A solution of
2-amino-5-methylbenzoic acid (15.08 g, 99.9 mmol) and methyl
isocyanate (7.0 mL, 120 mmol) in 450 mL of dry benzene was
refluxed for 2 h. Benzene was evaporated, and the resulting
brown solid was treated with 200 mL of 6 M H2SO4 and heated
under reflux for 1 h. After standing overnight, the solid was
filtered and washed with water until the pH of the filtrate was
6-7. After drying in an oven at 80-85 °C overnight, 12 was
obtained as a white solid (14.16 g, 75%): mp 258-259 °C; 1H
NMR (CDCl3) δ 9.91 (br) (s, 1 H), 7.94 (m, 1 H, J ) 1.2 Hz),
7.43 (dd, 1 H, J ) 1.5, 8.3 Hz), 7.03 (d, 1 H, J ) 8.3 Hz), 3.49
(s, 3 H), 2.41 (s, 3 H); 13C (DMSO-d6) δ 162.4, 150.5, 137.4,
136.1, 131.8, 126.9, 115.2, 113.7, 27.2, 20.5; IR (DMSO-d6) 3445