A R T I C L E S
Stoncˇius et al.
1-Benzyl-4-hydrazino-6-methyl-2(1H)-pyridinone (7). Method
A: To a solution of 11 (540 mg, 2.31 mmol) in methanol (20 mL)
was added hydrazine monohydrate (1.12 mL, 23.1 mmol), and the
resulting mixture was heated under reflux for 30 h. Cooled reaction
mixture was evaporated to dryness, and the remaining solid was purified
by flash chromatography (10:1 CHCl3/MeOH) to afford 7 (430 mg,
81%) as a brownish solid, mp 218-220 °C. Method B: Finely
powdered 9 (100 mg, 0.46 mmol) and hydrazine hydrate (204 µL, 4.2
mmol) were placed into a 15 mL pressure tube (Ace, with Teflon
bushing and FETFE O-ring, length 10.2 cm). The reaction tube was
placed in a beaker filled with vermiculite and irradiated in an ordinary
domestic microwave oven (Zanussi ZM17M with rotate plate) for 6
min at 250 W. The reaction could not be performed in more than ca.
0.5 mmol scale since too high pressure develops and hydrazine hydrate
escapes from the reaction vessel. The reaction mixture was cooled, the
residue dissolved in methanol, and collected. The procedure was
repeated four more times (in total 500 mg, 2.3 mmol of 6); the combined
solutions were evaporated to dryness, and the remaining solid was
purified by flash chromatography (10:1 CHCl3/MeOH) to afford 7 (300
mg, 57%) as a brownish solid, mp 218-220 °C; Rf 0.19 (10:1 CHCl3/
MeOH); IR ν 3259, 3194 (NH), 1652 (CdO), 1573, 1531, 818, 721;
1H NMR (400 MHz, DMSO-d6) δ 7.51 (1H, s, NH), 7.33-7.28 (2H,
m, H-Ph), 7.25-7.20 (1H, m, H-Ph), 7.08-7.07 (2H, m, H-Ph),
5.61 (1H, bs, H-3), 5.49 (1H, d, J ) 2.1 Hz, H-5), 5.13 (2H, s, H-CH2-
Ph), 4.12 (2H, bs, NH), 2.07 (3H, s, H-CH3); 13C NMR (100.6 MHz,
DMSO-d6) δ 163.8 (C-2), 158.1 (C-4), 145.2 (C-6), 138.8 (Ph), 128.7
(2C, Ph), 126.9 (Ph), 126.3 (2C, Ph), 96.9 (C-3), 87.6 (C-5), 44.9
(2C, CH2-Ph), 20.2 (CH3); MS, m/z (%) 231 ([M + 2]+, 17), 230
([M + 1]+, 100), 229 ([M - 1]+, 34), 154 (16), 136 (11), 91 (42).
HRMS (FAB+) calcd for C13H16N3O ([M + H]+) 230.1293, found
230.1292.
General Procedure for the Alkylation of Methanocyclooctadi-
indole (6R,13R)-6. In a round-bottomed flask, NaH (22 mg, 0.56 mmol,
60% dispersion in mineral oil) was washed with dry hexane (2 × 2
mL), and solid (6R,13R)-6 (100 mg, 0.185 mmol) was added. The flask
was flushed with nitrogen, and dry DMF (25 mL) was added. The
reaction mixture was stirred under nitrogen at room temperature until
evolution of hydrogen ceased and a clear solution was obtained (ca. 2
h). To the resulting solution were added 1-iododecane (237 µL, 1.1
mmol) or 1-bromodecane (230 µL, 1.1 mmol; together with a catalytic
amount of KI) and 1-bromobutane (119 µL, 1.1 mmol; together with
a catalytic amount of KI) in dry DMF (1 mL) dropwise, and the mixture
was stirred for 24 h. DMF was removed by co-distillation with toluene;
the obtained residue was suspended in chloroform and filtered through
a short plug of silica gel eluting with chloroform. The filtrate was
evaporated to dryness and the residue purified by flash chromatography
to afford alkylated methanocyclooctadiindoles.
(-)-(6R,13R)-2,9-Dibenzyl-5,12-dibutyl-2,9-diaza-3,10-dimethyl-
1,8-dioxo-2,5,6,7,9,12,13,14-octahydro-6,13-methanocycloocta[1,2-
b:5,6-b′]diindole (13). Yellow solid, yield 69 mg (57%), mp >250
20
°C (dec); Rf 0.23 (2:3 heptane/ethyl acetate); [R]D ) -380 (c 0.05,
CHCl3); UV (in CHCl3), λmax (log ꢀ) 318 (4.3, sh), 307 (4.37), 284
(4.26, sh), 231 (4.46); CD (in CHCl3), λmax (∆ꢀ/dm3 mol-1 cm-1) 322
(-48.99), 310 (-46.65), 288 (0), 282 (7.45), 270 (0), 260 (-5.88).
1
IR: ν 2955, 2928 (CH), 1652 (CdO), 1590; H NMR (400 MHz) δ
7.26-7.23 (4H, m, H-Ph), 7.19-7.16 (2H, m, H-Ph), 7.13-7.11 (4H,
m, Ph), 6.09 (2H, d, J ) 0.6 Hz, H-4(11)), 5.33 (4H, br dd, 2J ) 15.6
2
3
Hz, H-CH2Ph), 4.03 (2H, dt, J ) 14.8 Hz, J ) 7.5 Hz, H-CH2N(5,-
2
3
12)), 3.91 (2H, dt, J ) 14.8 Hz, J ) 7.5 Hz, H-CH2N(5,12)), 3.40
(2H, t, 3J ) 2.8 Hz, H-6(13)), 3.31-3.21 (4H, m, H-7(14)), 2.26 (6H,
3
s, H-CH3), 2.16 (2H, t, J ) 2.8 Hz, H-15), 1.73 (4H, quint, J ) 7.5
Hz), 1.47-1.34 (4H, m), 0.97 (6H, t, 3J ) 7.4 Hz, H-C3H7); 13C NMR
(100.6 MHz) δ 160.8 (C-1(8)), 138.2 (C-3(10)), 137.9 (C-4a(11a)),
137.5 (Ph), 134.2 (C-5a(12a)), 128.5 (2C, Ph), 126.69 (Ph), 126.3 (2C,
Ph), 112.0 (C-7b(14b)), 111.3 (C-7a(14a)), 94.7 (C-4(11)), 46.0 (CH2-
Ph), 43.3 (C-N(5,12)), 33.1, 30.4 (C-6(13)), 29.1 (C-15), 26.2 (C-
7(14)), 21.2, 20.3 (CH3), 13.8; MS, m/z (%) 654 ([M + 2]+, 30), 653
([M + 1]+, 85), 652 ([M]+, 100), 651 ([M - 1]+, 26), 154 (23), 136
(14), 91 (31). Anal. Calcd for C43H48N4O2: C, 79.11; H, 7.41; N, 8.58.
Found: C, 79.31; H, 7.68; N, 8.72. HRMS (FAB+) calcd for
C43H48N4O2 ([M]+) 652.3777, found 652.3787.
(1S,5S)-Bicyclo[3.3.1]nonane-2,6-dione bis[(1-benzyl-6-methyl-2-
oxo-1,2-dihydro-4-pyridinyl)hydrazone] 12. Hydrazine 7 (500 mg,
2.19 mmol) and (+)-(1S,5S)-2 (150 mg, 1.00 mmol) were dissolved in
methanol with heating. The resulting clear solution was refluxed for 5
h. The reaction mixture was cooled, the precipitate was filtered, washed
twice with cold solvent, and dried in vacuo to afford the hydrazone as
a mixture of E,E and E,Z isomers, which was used without further
purification. Yield 550 mg (95%), white solid, mp >320 °C; IR ν 3418,
3228 (NH), 1643 (CdO), 1564, 1531, 1236, 825; MS, m/z (%) 575
([M + 1]+, 23), 307 (47), 298 (18), 154 (100), 136 (74), 107 (22), 91
(28), 89 (22). Anal. Calcd for C35H38N6O2: C, 73.14; H, 6.66; N, 14.62.
Found: C, 72.98; H, 6.58; N, 14.78. HRMS (FAB+) calcd for
C35H39N6O2 ([M + H]+) 575.3134, found 575.3121.
(-)-(6R,13R)-2,9-Dibenzyl-5,12-didecyl-2,9-diaza-3,10-dimethyl-
1,8-dioxo-2,5,6,7,9,12,13,14-octahydro-6,13-methanocycloocta[1,2-
b:5,6-b′]diindole (14). Yellow glass, yield 126 mg (83%), mp 81-83
°C; Rf 0.22 (7:3 heptane/ethyl acetate); [R]D20 ) -244 (c 0.073, CHCl3);
UV (in CH2Cl2), λmax (log ꢀ) 319 (4.28, sh), 306 (4.36), 285 (4.23, sh),
220 (4.8, sh); CD (in CH2Cl2) λmax (∆ꢀ/dm3 mol-1 cm-1) 321 (-46.24),
310 (-43.28), 288 (0), 280 (11.86), 267 (0), 257 (-5.93). IR: ν 2925,
(6R,13R)-2,9-Dibenzyl-2,9-diaza-3,10-dimethyl-1,8-dioxo-2,5,6,7,9,-
12,13,14-octahydro-6,13-methanocycloocta[1,2-b:5,6-b′]diindole (6).
A round-bottomed flask equipped with an air condenser and rubber
septum was charged with hydrazone (1S,5S)-12 (500 mg, 0.87 mmol)
and diphenyl ether (25 mL). The suspension was stirred and heated at
reflux, passing argon through the mixture via a long cannula. After
7.5-8 h, the evolution of ammonia ceased and the reaction mixture
was cooled, diluted with pentane, and filtered. The precipitate was
washed with diethyl ether and diethyl ether-methanol mixture (1:1
v/v) to give 440 mg (94%) of (6R,13R)-6 as a gray solid, mp >320
1
2853 (CH), 1654 (CdO), 1590, 729; H NMR (400 MHz) δ 7.27-
7.23 (4H, m, H-Ph), 7.19-7.16 (2H, m, H-Ph), 7.12-7.11 (4H, m,
H-Ph), 6.09 (2H, d, J ) 0.5 Hz, H-4(11)), 5.33 (4H, br dd, H-CH2-
Ph), 4.02 (2H, dt, 2J ) 15 Hz, 3J ) 7.5 Hz, H-CH2N(5,12)), 3.89 (2H,
2
3
dt, J ) 15 Hz, J ) 7.5 Hz, H-CH2N(5,12)), 3.39 (2H, bs, H-6(13)),
3.31-3.21 (4H, m, H-7(14)), 2.26 (6H, s, H-CH3), 2.15 (2H, bs, H-15),
1.8-1.67 (4H, m), 1.4-1.26 (28H, m), 0.88 (6H, t, 3J ) 7 Hz,
H-C9H19); 13C NMR (100.6 MHz) δ 160.8 (C-1(8)), 138.2 (C-3(10)),
137.9 (C-4a(11a)), 137.5 (Ph), 134.2 (C-5a(12a)), 128.5 (2C, Ph), 126.7
(Ph), 126.4 (2C, Ph), 112.1 (C-7b(14b)), 111.3 (C-7a(14a)), 94.7 (C-
4(11)), 46.0 (CH2-Ph), 43.6 (C-N(5,12)), 31.9, 31.0, 30.4 (C-6(13)),
29.7 (C-15), 29.5, 29.5, 29.3, 29.2, 27.1, 26.3 (C-7(14)), 22.7, 21.3
(CH3), 14.1; MS, m/z (%) 822 ([M + 2]+, 40), 821 ([M + 1]+, 88),
820 ([M]+, 100), 819 ([M - 1]+, 35), 429 (10), 339 (9), 91 (51). Anal.
Calcd for C55H72N4O2: C, 80.44; H, 8.84; N, 6.82. Found: C, 80.77;
H, 9.09; N, 6.69. HRMS (FAB+) calcd for C55H72N4O2 ([M]+)
820.5655, found 820.5666.
1
°C; IR ν 3398, 3281 (NH), 1641 (CdO), 1575; H NMR (400 MHz,
11 mg in 0.7 mL of CDCl3/0.02 mL of TFA) δ 10.01 (2H, s, NH),
7.3-7.25 (6H, m, H-Ph), 6.97-6.95 (4H, m, H-Ph), 6.91 (1H, s,
2
2
H-4(11)), 5.59 (2H, d, J ) 16.2 Hz, H-CH2Ph), 5.47 (2H, d, J )
16.2 Hz, H-CH2Ph), 3.53 (2H, d, J ) 2.6 Hz, H-6(13)), 3.34 (2H, d, 2J
) 16.3 Hz, Hendo-7(14)), 3.16 (2H, dd, 2J ) 16.3 Hz, 3J ) 5 Hz, Hexo
-
7(14)), 2.48 (6H, s, H-CH3), 2.17 (2H, bs, H-15); 13C NMR (100.6
MHz, 11 mg in 0.7 mL of CDCl3/0.02 mL of TFA) δ 156.1 (C-1(8)),
142.1 (C-3(10)), 139.3 (C-4a(11a)), 139.2 (Ph), 134.2 (C-5a(12a)), 129.1
(2C, Ph), 128.1 (Ph), 125.8 (2C, Ph), 111.5 (C-7b(14b)), 110.8 (C-7a-
(14a)), 103.9 (C-4(11)), 49.6 (CH2-Ph), 28.7 (C-6(13)), 28.3 (C-15),
27.4 (C-7(14)), 20.7 (CH3).
(-)-(6R,13R)-5,12-Dibutyl-2,9-diaza-3,10-dimethyl-1,8-dioxo-
2,5,6,7,9,12,13,14-octahydro-6,13-methanocycloocta[1,2-b:5,6-b′]di-
9
8284 J. AM. CHEM. SOC. VOL. 128, NO. 25, 2006