Bobeck et al.
JOCArticle
was heated at reflux for 2 h. After being cooled to rt, the solvent
was removed under reduced pressure. The yellow residue that
remained was purified by flash column silica gel chromatography
to give the Z-substituted thiolactam 52 (0.48 g, 71%) as a light
yellow oil: IR (neat) 3306, 3176, 3065, 1737, 1523, 1348, and 1239
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.61-1.94 (m, 7H), 2.01 (s,
3H), 2.07-2.18 (m, 2H), 2.29-2.36 (m, 1H), 3.15-3.27 (m, 2H),
4.07-4.25 (m, 2H), 5.74-5.81 (m, 1H), 6.69 (d, 1H, J=11.4 Hz),
7.38-7.42 (m, 2H), 7.57 (dt, 1H, J=7.4 and 1.2 Hz), 7.98 (dd, 1H,
J=8.6 and 1.2 Hz), and 9.15 (brs, 1H); 13C NMR (CDCl3, 100
MHz) δ 19.3, 21.2, 23.7, 28.5, 40.3, 41.9, 45.3, 47.4, 61.3, 124.6,
125.9, 128.0, 132.1, 132.7, 133.1, 133.7, 148.3, 171.2 and 209.1;
HRMS calcd for [C19H25N2O4S þ Hþ] 377.1535, found
377.1530.
(Z)-9-(2-Acetoxyethyl)-9-(4-(2-nitrophenyl)but-3-enyl)-2-oxo-6,
7,8,9-tetrahydro-2H-pyrido[2,1-b][1,3]thiazin-5-ium-4-olate (53).
To a solution containing 0.12 g (0.32 mmol) of thioamide 52 in
CH2Cl2 (5.5 mL) at -78 °C was added carbon suboxide, pre-
pared from 0.19 g (2.9 mmol) of zinc dust and 0.67 g (2.2 mmol)
of dibromomalonyl dichloride in refluxing Et2O (11 mL) for
20 min. The resulting yellow solution was stirred for an additional
45 minat rt. The solvent was removed under reduced pressure, and
the resulting mixture was purified by flash column silica gel
chromatography to give dipole 53 (0.11 g, 80%) as a bright yellow
oil: IR (neat) 2954, 1738, 1646, and 1522 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.81-2.05 (m, 8H), 1.98 (s, 3H), 2.07-2.16 (m, 1H),
2.33 (ddd, 1H, J=14.9, 8.6, and 6.3 Hz), 3.94-4.01 (m, 1H), 4.03-
4.16 (m, 2H), 4.26 (ddd, 1H, J=11.7, 6.7, and 5.1 Hz), 5.23 (s, 1H),
5.73 (dt, 1H, J=11.3 and 7.4 Hz), 6.79 (d, 1H, J=11.3 Hz), 7.26 (d,
1H, J=7.4 Hz), 7.48 (dt, 1H, J=8.2 and 1.2 Hz), 7.62 (dt, 1H, J=
7.4 and 1.2 Hz), and 8.03 (dd, 1H, J=8.2 and 1.2 Hz); 13C NMR
(CDCl3, 100 MHz) δ 19.3, 20.8, 23.3, 29.0, 42.2, 43.8, 47.9, 48.1,
59.6, 88.0, 125.0, 128.2, 128.9, 130.7, 131.5, 131.9, 133.4, 148.3,
161.6, 166.2, 170.6, and 193.7.
and was then poured into brine (20 mL) and extracted with
CHCl3. The combined organic mixture was dried over anhy-
drous MgSO4 and filtered, and the solvent was removed under
reduced pressure. Purification of the residue by flash column
chromatography on deactivated (2% NEt3) silica gel gave
the title compound 59 (5.7 mg, 21% over three steps) as a light
yellow oil: IR (CH2Cl2) 3313, 2951, 1734, 1647, 1403, and
1242 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.49-1.75 (m,
;
6H), 1.86-2.01 (m, 3H), 2.06 (s, 3H), 2.13-2.22 (m, 1H), 2.31
(ddd, 1H, J=15.7, 13.3, and 0.8 Hz), 2.53 (dd, 1H, J=15.7 and
5.1 Hz), 2.79-2.86 (m, 1H), 3.25 (dd,1H, J=13.3 and 4.7 Hz),
3.89 (s, 1H), 4.13-4.24 (m, 2H), 4.41-4.46 (m, 1H), 4.81 (s, 1H),
6.79 (d, 1H, J=7.8 Hz), 6.88 (dt, 1H, J=7.4 and 0.8 Hz), and
7.08-7.14 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 18.8, 21.4,
29.1, 29.2, 34.0, 36.9, 39.1, 39.5, 48.0, 48.4, 61.7, 76.4, 91.6,
111.8, 121.8, 124.4, 128.6, 130.7, 147.7, 171.4, and 174.4.
2- (7-Oxo-2,2a,2a0,3,4,5,7,8,8a,13-decahydro-1H-cyclopenta-
[ij]indolo[2,3-a]quinolizin-2a-yl)ethyl Acetate (60). To a stirred
solution of 9.0 mg (0.024 mmol) of pentacycle 59 in AcOH (2
mL) and H2O (1.0 mL) at rt was added 24 mg (0.38 mmol) of
NaBH3CN in one portion. The reaction mixture was stirred at rt
for 30 min and then heated at 50 °C for an additional 2 h. The
reaction mixture was cooled to rt and was then carefully poured
into a saturated aqueous NaHCO3 solution and extracted with
CHCl3. The combined organic extracts were dried over anhy-
drous MgSO4 and filtered, and the solvent was removed under
reduced pressure. Purification of the residue by flash column
silica gel chromatography gave 60 (5.9 mg, 69%) as a white
solid: mp 143-144 °C; IR (neat) 3360, 2924, 2854, 1738, 1645,
and 1465 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.57-1.72 (m,
6H), 1.81-2.07 (m, 5H), 2.09 (s, 3H), 2.42 (dd, 1H, J=15.6 and
12.0 Hz), 2.51-2.58 (m, 2H), 3.22 (dd, 1H, J=11.7 and 4.7 Hz),
3.43 (s, 1H), 4.16-4.29 (m, 2H), 4.43-4.48 (m, 1H), 6.66 (d, 1H,
J=7.8 Hz), 6.76 (t, 1H, J=7.2 Hz), and 7.06-7.09 (m, 2H); 13
C
2-(1-(2-Nitrophenyl)-3-oxo-2,3,5,6,7,7a,8,9-octahydro-1H-cyclo-
penta[ij]-quinolizin-7a-yl)ethyl Acetate (56). A solution of 0.52 g
(1.2 mmol) of dipole 53 in toluene (11 mL) in a sealed tube was
placed in a preheated oil bath at 200 °C for 1 h. The dark mixture
was cooled to rt, and the solvent was removed under reduced
pressure. The residue was purified by flash column silica gel
chromatography to give tricycle 56 (0.14 g, 31%) as a yellow
solid: mp 118-121 °C; IR (CDCl3) 2939, 2859, 1737, 1673, and
1525 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.37-1.29 (m, 1H),
1.60-1.68 (m, 1H), 1.78-1.87(m, 4H), 1.91-2.00 (m, 2H), 2.02-
2.17 (m, 2H), 2.09 (s, 3H), 2.69(dd, 1H, J=14.9 and 14.5 Hz), 2.95
(dd, 1H, J=15.4 and 5.7 Hz), 3.01-3.09 (m,1H), 4.01 (dt, 1H, J=
12.9 and 3.9 Hz), 4.10-4.22 (m, 2H), 4.34-4.39 (m, 1H), 7.35-
7.42 (m, 2H), 7.62 (dt, 1H, J=7.8 and 1.2 Hz), and 7.80 (dd, 1H,
J=7.8 and 1.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 19.5, 21.2,
28.4, 33.1, 33.3, 34.9, 37.0, 40.1, 41.2, 44.7, 61.8, 115.9, 124.5,
127.9, 130.0, 133.2, 136.6, 142.6, 150.3, 169.8, and 171.3; HRMS
calcd for C21H24N2O5 385.1763, found 385.1756.
2-(2a0-Hydroxy-7-oxo-2,2a,2a0,3,4,5,7,8,8a,13-decahydro-1H-
cyclopenta[ij]-indolo[2,3-a]quinolizin-2a-yl)ethyl Acetate (59). A
mixture of 28 mg (0.073 mmol) of tricycle 56, 28 mg of 10% Pd/C
in EtOH (2.2 mL), and THF (1 mL) was stirred under an H2
atmosphere (4 atm) at rt for 15 h. The reaction mixture was
filtered through a pad of Celite with EtOAc. The solvent was
removed under reduced pressure, and the crude aniline 58 was
used in the next step without purification. To the above aniline
58 in CH2Cl2 (5 mL) at rt was added 6 mg (0.03 mmol) of N-
bromosuccinimide in one portion. The orange mixture was
stirred at rt for 20 min, and then the solvent was removed under
reduced pressure without heating. The crude bromide was used
immediately in the next step without purification.
NMR (CDCl3, 100 MHz) δ 19.1, 21.3, 30.5, 34.2, 36.7, 38.7,
39.1, 40.2, 44.0, 47.0, 61.3, 70.3, 76.0, 110.0, 119.6, 124.3, 128.4,
130.4, 149.0, 171.4, and 172.7; HRMS Calcd for C21H26N2O3
355.2022, found 355.2015.
2- (2,2a,2a0,3,4,5,7,8,8a,13-Decahydro-1H-cyclopenta[ij]indo-
lo[2,3-a]quinolizin-2a-yl)ethyl Acetate (62). A solution of 27 mg
(0.07 mmol) of pentacycle 60 and 17 mg (0.04 mmol) of Law-
esson’s reagent in toluene (2 mL) was heated at reflux for 2 h.
The reaction mixture was cooled to rt, and the solvent was
removed under reduced pressure. The dark yellow residue was
passed through a short plug of silica gel to give (26 mg, 93%) of
61 as a yellow oil that was used without further purification in
the next reaction. To a stirred suspension of Ra-Ni under N2 in
THF (1 mL) was added a solution of 9.8 mg (0.026 mmol) of the
above thiolactam 61 in THF (1.5 mL) at rt. After the hetero-
geneous mixture was stirred under a H2 balloon for 1.5 h, the
reaction mixture was filtered through Celite. The solvent was
removed under reduced pressure. Purification of the residue by
preparative TLC on silica gel gave the title compound 62 (5.6
mg, 64%) as a colorless oil: IR (neat) 3411, 1732, 1608, 1463, and
1245 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.44-1.50 (m, 3H),
1.54-1.62 (m, 2H), 1.72-1.84 (m, 1H), 1.87-2.04 (m, 7H),
2.07-2.13 (m, 1H), 2.08 (s, 3H), 2.20-2.29 (m, 1H), 2.52-2.57
(m, 1H), 2.66-2.71 (m, 1H), 3.24 (t, 1H, J=4.3 Hz), 4.04 (dt, 1H,
J=10.6 and 5.5 Hz), 4.31 (dt, 1H, J=10.6 and 5.5 Hz), 4.47 (brs,
1H), 6.65 (d, 1H, J=7.4 Hz), 6.72 (t, 1H, J=7.4 Hz), and 6.99-
7.04 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 19.5, 21.3, 24.9,
30.1, 35.0, 35.8, 39.2, 44.1, 45.0, 50.7, 53.3, 61.8, 75.2, 75.3,
109.2, 118.6, 122.9, 127.6, 131.6, 150.2, and 171.6; HRMS calcd
for C21H28N2O2 341.2229, found 341.2222.
2- (2,2a,2a0,3,4,5,7,8,8a,13-Decahydro-1H-cyclopenta[ij]indo-
lo[2,3-a]quinolizin-2a-yl)ethanol (63). To a solution containing
5.6 mg (0.016 mmol) of 62 in MeOH (1 mL) at 0 °C was added
4.5 mg (0.033 mmol) of K2CO3. After the mixture was stirred for
To the above bromide in MeOH (0.5 mL) at rt was added a
solution of 13 mg (0.078 mmol) of AgNO3 in H2O (6 mL) and
MeOH (1.5 mL). The reaction mixture was stirred at rt for 1 h
J. Org. Chem. Vol. 74, No. 19, 2009 7401