Cyclizations of Substituted Benzylidene-3-alkenylamines
J . Org. Chem., Vol. 65, No. 3, 2000 665
quenched with DMS (2.0 mL), allowed to warm to room
temperature, and then was concentrated under reduced pres-
sure. The crude product was purified by silica gel chromatog-
raphy with hexanes/EtOAc (5:1) to give 3.13 g (78%) as a white
solid: mp 100.5-101 °C; 1H NMR (400 MHz, CDCl3) δ 1.42 (t,
J ) 7.1 Hz, 3H), 1.55 (s, 9H), 4.40 (q, J ) 7.1 Hz, 2H), 8.20
(dd, J ) 8.9, 1.7 Hz, 1H), 8.34 (d, J ) 1.8 Hz, 1H), 8.55 (d, J
) 8.9 Hz, 1H), 9.96 (s, 1H), 10.60 (br s, 1H); 13C NMR (100.6
MHz, CDCl3) δ 14.3, 28.2, 61.2, 81.3, 117.9, 120.5, 123.6, 136.7,
137.9, 145.3, 152.4, 165.1, 194.6; IR (KBr) 3250, 2985, 1715,
1695 cm-1; MS (CI) m/z 294 (M+ + H), 255, 238, 194, 57. Anal.
Calcd for C15H19NO5: C, 61.42; H, 6.53; N, 4.78. Found: C,
61.45; H, 6.83; N, 4.80.
(N′-ter t-Bu t oxyca r b on yl-2′-a m in o-5′-ca r b et h oxyb en -
zylid en e)-[(Z)-5-(tr im eth ylsilyl)-3-p en ten yl]a m in e (62). A
solution of 21 (0.12 g, 0.65 mmol) and triphenylphosphine (0.17
g, 0.65 mmol) in THF (5.0 mL) was stirred at room tempera-
ture for 3 h. Next, 61 (0.19 g, 0.65 mmol) was added, and the
reaction was heated at reflux for 20 h. The reaction was then
cooled to room temperature, concentrated under reduced
pressure, triturated with ether, filtered through Florisil, and
concentrated under reduced pressure to give 0.35 g of a crude
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 9H), 1.39
(t, J ) 7.0 Hz, 3H), 1.54 (s, 9H), 2.40 (q, J ) 6.8 Hz, 2H), 3.64
(t, J ) 6.7 Hz, 2H), 4.36 (q, J ) 7.2 Hz, 1H), 5.42 (m, 1H),
5.50 (m, 1H), 8.00 (m, 2H), 8.37 (s, 1H), 8.46 (d, J ) 9.3 Hz,
1H), 12.38 (br s, 1H); 13C NMR (100.6 MHz, CDCl3) δ -1.8,
14.4, 18.7, 28.3, 28.7, 60.8, 61.0, 80.3, 117.4, 119.6, 122.8, 123.9,
127.5, 132.4, 134.7, 144.7, 153.2, 163.1, 165.9; IR (film) 2960,
2940, 1715, 1700 cm-1; MS (CI) m/z 433 (M+ + H), 377, 279,
263, 208, 194, 183; HRMS calcd for C23H37N2O4Si 433.2522,
found 433.2526. This compound was used immediately in the
next step without further purification.
product was purified by silica gel chromatography with hex-
anes/EtOAc (2:1) to give 2.8 g (91%) of a yellow solid as a 17:3
mixture of diastereomers, based on 1H NMR integration, mp
148.5-151.5 °C. Major isomer, (1R*,10bR*)-64: 1H NMR (400
MHz, CDCl3) δ 1.37 (t, J ) 7.1 Hz, 3H), 1.98 (dd, J ) 12.6, 6.9
Hz, 1H), 2.25 (m, 1H), 2.46 (s, 3H), 3.44 (m, 1H), 3.54 (m, 1H),
3.79 (m, 1H), 4.36 (m, 1H), 4.81 (d, J ) 4.7 Hz, 1H), 5.07 (d, J
) 9.9 Hz, 1H), 5.25 (dd, J ) 17.0, 1.3 Hz, 1H), 5.34 (m, 1H),
7.38 (d, J ) 8.1 Hz, 2H), 7.51 (d, J ) 8.7 Hz, 1H), 7.75 (s, 1H),
7.94 (dd, J ) 8.7, 1.1 Hz, 1H), 7.98 (m, 1H), 8.15 (d, J ) 8.3
Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 14.1, 21.2, 30.2, 44.2,
45.1, 59.4, 60.9, 118.2, 120.4, 126.2, 126.6, 128.0, 128.7, 128.8,
129.3, 129.5, 134.8, 137.1, 139.0, 144.6, 148.9; IR (KBr) 2960,
2880, 1705 (sh), 1690 cm-1; MS (CI) m/z 441 (M+ + H). Anal.
Calcd for C23H24N2O5S: C, 62.71; H, 5.49; N, 6.36. Found: C,
62.35; H, 5.72; N, 6.37. Minor isomer, (1R*,10bS*)-64 (diag-
nostic peaks only): 1H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H),
3.05 (m, 1H), 3.38 (m, 1H), 3.82 (m, 1H), 4.50 (d, J ) 9.6 Hz,
1H), 5.42 (m, 1H), 6.01 (m, 1H), 7.30 (d, J ) 8.0 Hz, 2H), 7.46
(d, J ) 8.6 Hz, 1H), 7.81 (d, J ) 8.2 Hz, 1H), 8.19 (d, J ) 8.3
Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 14.0, 21.4, 30.9, 44.6,
48.2, 59.0, 117.8, 120.2, 125.2, 126.1, 127.3, 128.1, 129.1, 130.2,
137.2, 139.2.
(2R*,3R*)- a n d (2R*,3S*)-2-(5′-Ca r bom eth oxy-2′-p-tolu -
en esu lfon yla m in op h en yl)-3-eth en ylp yr r olid in e (65). A
solution of 64 (2.50 g, 5.68 mmol) in THF/MeOH/50% aqueous
NaOH (3:2:1, 120 mL) was heated at reflux for 67 h. The
reaction was acidified to pH ∼1 with 10% HCl and extracted
with CH2Cl2 (3 × 200 mL). The combined organic layers were
dried (Na2SO4), decanted, and concentrated under reduced
pressure to give 2.41 g of crude 2-(5′-carboxy-2′-p-toluenesulfo-
nylaminophenyl)-3-ethenylpyrrolidine as a brown oil: IR (KBr)
3650-2300 (br), 3400, 3050, 1645 cm-1; MS (CI) m/z 387 (M+
+ H), 259, 189; HRMS calcd for C20H23N2O4S 387.1378, found
387.1375. To a solution of the crude acid (2.41 g) in MeOH
(100 mL) was added concentrated H2SO4 (0.5 mL). The reaction
was heated at reflux for 20 h, then cooled to room temperature
and concentrated. To the resulting residue was added satu-
rated aqueous NaHCO3 (50 mL). This aqueous solution was
extracted with CH2Cl2 (3 × 75 mL). The combined organic
layers were dried (Na2SO4), decanted, and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography with CH2Cl2/MeOH (19:1) to give 1.31 g (57%
over two steps) of a white foam as a 17:3 mixture of diaster-
(1R*,10bR*)- a n d (1R*,10bS*)-9-Ca r beth oxy-1-eth en yl-
2,3,6,10b -t et r a h yd r o-1H -p yr r olo[1,2-c]q u in a zolin -5-on e
(63). To a solution of 62 (9.13 g, ca. 21.1 mmol, as a ca. 2:1
1
mixture of Z and E isomers, based on H NMR integration) in
CH2Cl2 (500 mL) at room temperature was added TiCl4 (12.0
mL, 109 mmol). After 18 h, 10% aqueous NaOH (500 mL) was
added slowly, and the reaction mixture was extracted with
CH2Cl2 (3 × 400 mL). The combined organic layers were dried
(Na2SO4), decanted, and concentrated under reduced pressure.
The crude product was purified by silica gel chromatography
with EtOAc/hexanes (2:1) to give 4.83 g (80%) of a light yellow
solid as a 17:3 mixture of diastereomers, based on 1H NMR
integration, mp 161-164 °C. Major isomer, (1R*,10bR*)-63:
1H NMR (400 MHz, CDCl3) δ 1.37 (t, J ) 7.1 Hz, 3H), 2.02
(m, 1H), 2.24 (m, 1H), 3.32 (m, 1H), 3.59 (m, 1H), 3.81 (m,
1H), 4.33 (q, J ) 7.1 Hz, 2H), 4.87 (d, J ) 4.6 Hz, 1H), 5.03 (d,
J ) 10.6 Hz, 1H), 5.16 (d, J ) 17.2 Hz, 1H), 5.59 (m, 1H), 6.84
(d, J ) 8.4 Hz, 1H), 7.66 (s, 1H), 7.82 (dd, J ) 8.3, 1.7 Hz,
1H), 9.33 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 14.3, 29.0,
43.1, 45.6, 60.7, 61.5, 113.8, 117.4, 117.8, 123.7, 128.7, 129.9,
135.6, 141.7, 153.0, 166.1; IR (KBr) 3180, 2960, 1685, 1660
cm-1; MS (CI) m/z 287 (M+ + H), 232. Anal. Calcd for
1
eomers, based on H NMR integration. Major isomer, (2R*,3R*)-
65: 1H NMR (400 MHz, CDCl3) δ 1.90 (m, 1H), 2.12 (m, 1H),
2.35 (s, 3H), 2.99 (m, 1H), 3.11 (m, 1H), 3.36 (m, 1H), 3.82 (s,
3H), 4.53 (m, 2H), 4.70 (m, 1H), 5.28 (m, 1H), 7.23 (d, J )
8.1 Hz, 1H), 7.36 (d, J ) 8.7 Hz, 1H), 7.53 (d, J ) 2.0 Hz,
1H), 7.69 (dd, J ) 8.6, 2.0 Hz, 1H), 7.77 (d, J ) 8.3 Hz, 1H);
13C NMR (100.6 MHz, CDCl3) δ 21.4, 31.8, 45.1, 48.5, 51.8,
66.7, 116.3, 116.5, 122.9, 124.3, 126.8, 129.4, 129.5, 131.2,
136.5, 137.9, 143.2, 144.4, 166.6; IR (KBr) 3440 (br), 2930,
1690, 1590 cm-1; MS (CI) m/z 401 (M+ + H), 191; HRMS calcd
for C21H25N2O4S 401.1535, found 401.1559. Minor isomer,
(2R*,3S*)-65 (diagnostic peaks only): 1H NMR (400 MHz,
CDCl3) δ 1.74 (m, 1H), 2.16 (m, 1H), 2.34 (s, 3H), 3.18 (m,
1H), 3.29 (m, 1H), 3.82 (s, 3H), 4.46 (m, 1H), 4.85 (m, 1H),
5.52 (m, 1H), 7.21 (m, 1H), 7.48 (d, J ) 2.0 Hz, 1H), 7.52 (m,
1H), 7.72 (d, J ) 8.3 Hz, 1H), 7.76 (m, 1H); 13C NMR (100.6
MHz, CDCl3) δ 21.4, 31.2, 44.2, 49.2, 51.9, 68.9, 116.9, 118.3,
123.4, 125.9, 126.7, 129.5, 129.7, 131.2, 137.1, 137.8, 143.4,
166.6.
C
16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C, 67.09; H,
6.32; N, 9.55. Minor isomer, (1R*,10bS*)-63 (diagnostic peaks
only): 1H NMR (400 MHz, CDCl3) δ 1.36 (t, J ) 7.1 Hz, 3H),
1.91 (m, 1H), 3.00 (m, 1H), 3.67 (m, 1H), 4.32 (m, 2H), 4.47 (d,
J ) 9.6 Hz, 1H), 5.32 (d, J ) 10.7 Hz, 1H), 5.40 (d, J ) 17.1
Hz, 1H), 5.99 (m, 1H), 6.87 (d, J ) 8.4 Hz, 1H), 7.85 (dd, J )
8.4, 1.7 Hz, 1H), 8.11 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ
14.2, 30.6, 43.5, 50.1, 60.4, 60.6, 117.7, 121.0, 123.8, 126.3,
130.1, 138.3, 141.5, 153.3, 166.5.
(1R*,10bR*)- a n d (1R*,10bS*)-9-Ca r beth oxy-6-p-tolu -
en esu lfon yl-1-eth en yl-2,3,6,10b-tetr a h yd r o-1H-p yr r olo-
[1,2-c]qu in a zolin -5-on e (64). To a solution of 63 (2.0 g, 7.0
mmol) in THF (150 mL) at 0 °C was added NaH (60%
dispersion in mineral oil, 0.80 g, 20 mmol). After 45 min,
p-toluenesulfonyl chloride (1.6 g, 8.4 mmol) was added and the
reaction was allowed to warm to room temperature. After an
additional 22 h, saturated aqueous NH4Cl (100 mL) was added
slowly and the reaction mixture was extracted with EtOAc (3
× 150 mL). The combined organic layers were dried (Na2SO4),
decanted, and concentrated under reduced pressure. The crude
(3a R*,4R*,9bS*)-8-Ca r bom eth oxy-4-(iod om eth yl)-5-p-
tolu en esu lfon yl-2,3,3a ,4,5,9b-h exa h yd r o-1H-p yr r olo[3,2-
c]qu in olin e (66). To a solution of 65 (0.50 g, 1.2 mmol) in
CH3CN (30 mL) at room temperature was added iodine (3.0
g, 12 mmol). The reaction was heated at reflux for 21 h, then
cooled to room temperature, and diluted with Et2O (200 mL).
The resulting solution was washed with saturated NaHCO3
(20 mL) and 10% aqueous Na2S2O3 (3 × 25 mL). The combined
aqueous layers were extracted with Et2O (50 mL). The
combined organic layers were dried (Na2SO4), decanted, and
concentrated under reduced pressure. The crude product was
purified by silica gel chromatography with EtOAc/hexanes (2: