Using the Pummerer Cascade for Alkaloid Synthesis
J . Org. Chem., Vol. 65, No. 8, 2000 2377
1H-NMR (CDCl3, 300 MHz) δ 0.96 (d, 3H, J ) 6.7 Hz), 1.27
(m, 5H), 1.63 (m, 2H), 2.06 (m, 1H), 2.60 (m, 4H), 3.75 (s, 2H),
4.91 (m, 2H), 5.01 (s, 2H), 5.64 (m, 1H), 7.17 (d, 2H, J ) 7.2
Hz), and 7.31 (m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 14.2, 20.1,
22.4, 26.2, 35.7, 37.4, 37.6, 37.7, 46.9, 112.8, 125.9, 127.4, 128.8,
136.9, 144.1, 172.5, and 176.1; HRMS calcd for C19H27NO2S
333.1762, found: 333.1761.
(4.3 mmol) of 95% formic acid. The mixture was heated at 100
°C for 1 h, cooled to rt, diluted with water, extracted with ethyl
acetate, and dried over MgSO4. The solvent was removed
under reduced pressure, and the residue was purified by silica
gel chromatography to give 0.54 g (99%) of 42 as a white
solid: mp 87-88 °C; IR (CCl4) 1661, 1589, 1538, and 1455
1
cm-1; H-NMR (CDCl3, 300 MHz) δ 1.19 (d, 3H, J ) 7.0 Hz),
N-Ben zyl-2-(et h ylsu lfin yl)-N-(5-m et h ylh ep t -6-en oyl)-
a ceta m id e (37). Treatment of 4.1 g (12.4 mmol) of the above
sulfide with 2.9 g (13.7 mmol) of sodium periodate gave 4.1 g
(94%) of 37 as a colorless oil: IR (neat) 1694, 1455, 1379, and
1.35 (m, 1H), 1.71 (m, 3H), 2.61 (m, 3H), 5.35 (m, 2H), 6.58 (d,
1H, J ) 9.3 Hz), 7.12 (d, 2H, J ) 7.2 Hz), and 7.27 (m, 4H);
13C-NMR (CDCl3, 75 MHz) δ 19.1, 21.8, 27.2, 29.4, 30.8, 46.4,
117.7, 119.9, 126.2, 127.1,128.7, 136.7, 140.7, 143,6, and 163.1.
Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N, 5.53. Found:
C, 80.35; H, 7.61; N, 5.48.
This same compound was also prepared by the Raney-nickel
desulfurization of thioethyl pyridone 41 using standard reduc-
tive conditions.
1
1161 cm-1; H-NMR (CDCl3, 300 MHz) δ 0.95 (d, 3H, J ) 6.7
Hz), 1.23 (m, 2H), 1.37 (t, 3H, J ) 7.5 Hz), 1.54 (m, 2H), 2.04
(m, 1H), 2.54 (t, 2H, J ) 7.3 Hz), 2.88 (m, 2H), 4.18 (d, 1H, J
) 14.6 Hz), 4.40 (d, 1H, J ) 14.6 Hz), 4.99 (m, 4H), 5.61 (m,
1H), 7.16 (d, 2H, J ) 7.1 Hz), and 7.32 (m, 3H); 13C-NMR
(CDCl3, 75 MHz) δ 6.6, 20.1, 22.0, 35.6, 36.9, 37.6, 46.3, 47.2,
60.5, 1130, 126.0, 127.7, 129.0, 136.1, 143.9, 168.3, and 176.4.
Anal. Calcd for C19H27NO3S: C, 65.30; H, 7.79; N, 4.01.
Found: C, 65.17; H, 7.63; N, 3.92.
Acetic Acid 1-Ben zyl-5-m eth yl-2-oxo-1,2,5,6,7,8-h exah y-
d r oqu in olin -3-yl Ester (40). To a refluxing solution of 3.1 g
(30 mmol) of acetic anhydride and 2 mg of p-toluenesulfonic
acid in 50 mL of toluene was added dropwise 1.1 g (3.0 mmol)
of sulfoxide 37 in 2 mL of toluene. After being heated at reflux
for 1 h, the mixture was concentrated under reduced pressure,
and the residue was subjected to silica gel chromatography.
The major product eluted from the above chromatographic
separation contained 0.68 g (73%) of a colorless oil which was
identified as acetoxypyridone 40: IR (neat) 1769, 1660, 1612,
and 1555 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 1.19 (d, 3H, J )
7.0 Hz), 1.35 (m, 1H), 1.71 (m, 3H), 2.33 (s, 3H), 2.53 (m, 2H),
2.68 (m, 1H), 5.35 (brs, 2H), 7.13 (d, 2H, J ) 8.8 Hz), and 7.27
(m, 4H); 13C-NMR (CDCl3, 75 MHz) 619.1, 20.6, 21.7, 27.0,
29.4, 30.8, 47.0, 118.3, 126.3, 127.2, 128.7, 130.0, 136.2, 138.7,
141.0, 157.8, and 168.8; HRMS calcd for C19H21NO3 311.1521,
found 311.1531. Anal. Calcd for C19H21NO3: C, 73.28; H, 6.80;
N, 4.50. Found: C, 73.09; H, 6.77; N, 4.32.
1-Ben zyl-5-m eth yl-3,4,5,6,7,8-h exa h yd r o-1H-qu in olin -
2-on e (43). To a solution of 0.2 g (0.8 mmol) of 42 in 25 mL of
THF at -40 °C was added dropwise 1.6 mL of a 1 M solution
of L-Selectride in THF. The reaction mixture was stirred for
1 h, allowed to warm to 0 °C, and quenched with brine. The
organic layer was washed with an aqueous solution of 30%
H2O2 and a 10% NaOH solution and dried over MgSO4. The
solvent was removed under reduced pressure, and the residue
was purified by silica gel chromatography to give 0.16 g (77%)
of 43 as a colorless oil: IR (neat) 1666, 1388, and 1182 cm-1
;
1H-NMR (CDCl3, 300 MHz) δ 1.01 (d, 3H, J ) 7.0 Hz), 1.23
(m, 1H), 1.54 (m, 1 H), 1.67 (m, 2H), 2.06 (m, 3H), 2.21 (m,
2H), 2.56 (m, 2H), 4.82 (d, 1H, J ) 16.3 Hz), 4.92 (d, 1H, J )
16.3 Hz), and 7.22 (m, 5H); 13C-NMR (CDCl3, 75 MHz) δ 19.3,
20.1, 23.5, 25.8, 30.3, 31.9, 32.6, 43.8, 120.3,126.2,126.7,128.5,
131.7, 138.5, and 170.5. Anal. Calcd for C17H21NO: C, 79.96;
H, 8.29; N, 5.49. Found: C, 80.14; H, 8.26; N, 5.53.
(4a R,5S,8a S)-5-Meth yld eca h yd r oqu in olin -2-on e (44).
To a solution containing 0.08 g of 43 in 10 mL of EtOH was
added a catalytic amount of PtO2. The resulting mixture was
hydrogenated at 50 psi for 10 h, filtered through a pad of
Celite, and concentrated under reduced pressure. The residue
was chromatographed on silica gel to afford 0.07 g (86%) of
44 as a white solid: mp 148-149 °C (lit.54 mp 150-152 °C);
The minor product eluted from the column contained 0.12
g (13%) of a colorless oil which was identified as 1-benzyl-3-
(ethylsulfenyl)-5-methyl-5,6,7,8-tetrahydro-1H-quinolin-2-
one (41): IR (neat) 1639, 1588, 1537, and 1454 cm-1; 1H-NMR
(CDCl3, 300 MHz) δ 1.20 (d, 3H, J ) 6.9 Hz), 1.27 (m, 2H),
1.35 (t, 3H, J ) 7.3 Hz), 1.42 (m, 1 H), 1.71 (m, 3H), 2.53 (m,
1H), 2.69 (m, 1H), 2.91 (m, 2H), 5.35 (brs, 2H), 7.13 (d, 2H, J
) 6.5 Hz), and 7.26 (m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 13.6,
19.0, 22.0, 25.1,26.9, 29.4, 30.9, 47.0, 119.8, 126.4, 126.5, 127.0,
1
IR (neat) 3190, 2950, 1670, and 1600 cm-1; H-NMR (CDCl3,
300 MHz) δ 0.93 (d, 3H, J ) 6.5 Hz), 1.30-2.65 (m, 12H), 3.60
(m, 1H), and 6.53 (brs, 1H); 13C-NMR (CDCl3, 75 MHz) δ 19.2,
20.1, 23.2, 27.4, 27.7, 31.7, 33.8, 39.7, 52.2, and 172.3. Anal.
Calcd for C10H17NO: C, 71.81; H, 10.25; N, 8.37. Found: C,
71.69; H, 10.22; N, 8.36.
N-[(1-Ben zoyl-4-vin yl-2,3-dih ydr o-1H-in dol-3-yl)acetyl]-
2-(eth ylsu lfen yl)-N-m eth yla ceta m id e. Following the gen-
eral procedure, treatment of 1.4 g (4.3 mmol) of 2-(1-benzoyl-
4-vinyl-2,3-dihydro-lH-indol-3-yl)-N-methylacetamide (48)61 with
0.66 g (4.8 mmol) of acid chloride 13 gave 1.8 g (98%) of the
titled compound as a colorless oil: IR (neat) 1690, 1646, 1449,
and 1383 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 1.21 (t, 3H, J )
7.4 Hz), 2.52 (q, 2H, J ) 7.4 Hz), 2.93 (m, 2H), 3.16 (s, 3H),
3.61 (m, 2H), 3.92 (m, 2H), 4.28 (dd, 1H, J ) 11.5 and 8.4 Hz),
5.35 (d, 1 H, J ) 11 .1 Hz), 5.77 (d, 1H, J ) 17.5 Hz), 6.72 (dd,
1H, J ) 17.5 and 11.1 Hz), 7.22 (m, 1H), and 7.42 (m, 7H);
13C-NMR (CDCl3, 75 MHz) δ 14.2, 26.0, 31.2, 35.0, 37.1, 42.2,
56.4, 116.4, 120.5, 127.1, 128.2, 128.3, 130.3, 131.9, 132.4,
133.7, 136.2, 142.4, 168.8, 171.8, and 173.8; HRMS calcd for
128.6, 135.5, 136.6, 139.7, and 160.8; HRMS calcd for C19H23
NOS 313.1500, found: 313.1497.
-
Tr iflu or om eth a n esu lfon ic Acid 1-Ben zyl-5-m eth yl-2-
oxo-1,2,5,6,7,8-h exa h yd r oqu in olin -3-yl Ester . To a stirred
solution of 0.7 g (2.2 mmol) of pyridone 40 in 50 mL of
methanol was added 1 mL of a saturated aqueous solution of
potassium carbonate. The mixture was stirred for 30 min,
diluted with water, extracted with CHCl3, and dried over
MgSO4. The solvent was removed under reduced pressure, and
the crude hydroxypyridone was dissolved in 50 mL of CH2Cl2.
To this was added 0.44 g (4.4 mmol) of triethylamine followed
by 1.2 g (3.3 mmol) of N-phenyltrifluoromethanesulfonimide.
The resulting mixture was stirred for 2 h, diluted with water,
extracted with CHCl3, and dried over MgSO4. Removal of the
solvent under reduced pressure followed by silica gel chroma-
tography afforded 0.77 g (87%) of the titled compound as a
white solid: mp 97-98 °C; IR (CCl4) 1667, 1614, 1548, and
C
24H26N2O3S 422.1664, found 422.1662.
N-[(1-Ben zoyl-4-vin yl-2,3-dih ydr o-1H-in dol-3-yl)acetyl]-
2-(eth ylsu lfin yl)-N-m eth yla ceta m id e (47). Treatment of
0.5 g (1.1 mmol) of the above amide with 0.3 g (1.2 mmol) of
sodium periodate afforded 0.5 g (96%) of 47 as a colorless oil:
1
1427 cm-1; H-NMR (CDCl3, 300 MHz) δ 1.19 (d, 3H, J ) 6.9
Hz), 1.35 (m, 1H), 1.73 (m, 3H), 2.63 (m, 3H), 5.37 (m, 2H),
7.12 (d, 2H, J ) 6.9 Hz), and 7.27 (m, 4H); 13C-NMR (CDCl3,
75 MHz) δ 18.8, 21.6, 27.2, 29.1, 30.8, 47.3, 118.0, 126.3, 127.4,
128.8, 131.1, 135.4, 137.6, 144.6, and 157.1. Anal. Calcd for
IR (neat) 2929, 1690, 1646, 1449, and 1383 cm-1 1H-NMR
;
(CDCl3, 300 MHz) δ 1.31 (t, 3H, J ) 7.4 Hz), 2.80 (m, 4H),
3.13 (s, 3H), 3.83 (m, 2H), 4.04 (m, 1H), 4.25 (m, 2H), 5.37 (d,
1H, J ) 11.1 Hz), 5.78 (d, 1H, J ) 17.4 Hz), 6.71 (dd, 1H, J )
17.4 and 11.1 Hz), 7.22 (m, 1H), and 7.43 (m, 7H); 13C-NMR
(CDCl3, 75 MHz) δ 6.3, 30.9, 34.5, 41.3, 45.7, 56.0, 59.8, 116.5,
120.4, 126.9, 128.1,128.3, 130.2, 130.3, 132.2, 133.6, 136.0,
136.1, 142.3, 167.5, 168.6, and 173.8. Anal. Calcd for
C
18H18F3NO4S: C, 53.86; H, 4.52; N, 3.49. Found: C, 53.85;
H, 4.61; N, 3.44.
1-Ben zyl-5-m et h yl-5,6,7,8-t et r a h yd r o-1H -q u in olin -2-
on e (42). To a stirred solution of 0.9 g (2.1 mmol) of the above
triflate in 25 mL of DMF was added 0.08 g (0.1 mmol) of Pd-
(PPh3)2(OAc)2, 0.7 mg (6.4 mmol) of triethylamine, and 0.2 mg
C
24H26N2O4S: C, 65.73; H, 5.98; N, 6.39. Found: C, 65.58; H,
5.81; N, 6.36.