H.-G. Schmalz, A. Yu. Fedorov et al.
FULL PAPER
6.1, 60.7, 60.9, 87.9, 109.1, 138.3, 140.7, 140.7, 153.7, 153.1,
178.0 ppm. C12H15IO5 (366.15): calcd. C 39.36, H 4.13; found C
39.42, H 4.14.
1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.59–2.82 [m, 2 H,
CH2C(O)], 2.94–3.22 (m, 2 H, CH2Ar), 3.45 (s, 3 H, CH3), 3.70 (s,
3 H, CH3), 3.95 (s, 3 H, CH3), 3.96 (s, 3 H, CH3), 6.72 (s, 1 H, 4Ј-
H), 7.29–7.48 (m, 3 H, 5ЈЈ-H, 6ЈЈ-H, 7ЈЈ-H), 8.38 (m, 1 H, 4ЈЈ-
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 31.4, 33.2, 45.6,
56.3, 61.3, 61.5, 108.0, 109.9, 114.7, 115.4, 122.2, 122.9, 123.6,
1-(1H-Benzo[d][1Ј,2Ј,3Ј]triazol-1Ј-yl)-3-(2ЈЈ-iodo-3ЈЈ,4ЈЈ,5ЈЈ-trimeth-
oxyphenyl)propan-1-one (38): 1-methylsulfonyl-1H-benzotriazole
(0.364 g, 1.85 mmol) and triethylamine (0.36 mL, 2.6 mmol) were
added to a solution of acid 36 (0.68 g, 1.85 mmol) in THF (10 mL)
and the reaction mixture was stirred at 65 °C for 24 h. After evapo-
ration of all volatiles under reduced pressure the product was iso-
lated by using column chromatography on silica gel (eluent petro-
leum ether/EtOAc, 2:1) to give compound 38 (67 mg, 70%) as a
white solid. Rf = 0.55 (petroleum ether/EtOAc, 1:1), m.p. 86 °C. 1H
126.5, 138.0, 139.0, 141.4, 152.7, 154.5, 198.4 ppm. IR (ATR): ν =
˜
750, 920, 1017, 1087, 1126, 1195, 1233, 1316, 1340, 1394, 1461,
1490, 1493, 1594, 1627, 1632, 2851, 2935 cm–1. MS (EI, 70 eV): m/z
(%) = 139 (9), 146 (12), 175 (9), 193 (10), 205 (28), 222 (9), 248
(12), 276 (9), 292 (9), 308 (18), 320 (60), 351 (100) [M]+. C21H21NO4
(351.40): calcd. C 71.78, H 6.02, N 3.99; found C 71.93, H 6.04, N
3.98.
3
NMR (400 MHz, CDCl3, 25 °C): δ = 3.31–3.35 (t, J = 7.7 Hz, 2
H, ArCH2), 3.72–3.77 [t, 3J = 7.7 Hz, 2 H, CH2C(O)], 3.83 (s, 3 H,
OCH3), 3.85 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 6.78 (s, 1 H, 6Ј-
1Ј,2Ј,3Ј-Trimethoxybenzo[5Ј,6Ј:5,4]-6,7-dihydro-1-oxo-1H-cyclo-
hepta[3,2-b]-1ЈЈ-methyl-1H-indole Oxime (40): Ketone 39 (130 mg,
0.37 mmol), NH2OH·HCl (142 mg, 2.04 mmol) and pyridine
(164 μL, 2.04 mmol) were dissolved in absolute EtOH (1.85 mL)
under an argon atmosphere. The reaction mixture was stirred at
reflux temperatures for 24 h before brine (3 mL) and EtOAc (5 mL)
were added. The organic layer was separated, aqueous layer ex-
tracted with EtOAc (2ϫ 5 mL), combined organic extracts were
dried with Na2SO4 and all solvents were removed under reduced
pressure. After column chromatography on silica gel (eluent petro-
leum ether/EtOAc/EtOH, 3:1:0.05) compound 40 (113 mg, 83%)
was obtained as a yellow solid. Rf = 0.5 (EtOAc/petroleum ether,
3
3
H), 7.51 (t, J = 7.7 Hz, 1 H, 3-H), 7.67 (t, J = 7.7 Hz, 1 H, 2-H),
8.12 (d, 3J = 8.3 Hz, 1 H, 4-H), 8.30 (d, 3J = 8.3 Hz, 1 H, 1-H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 35.6, 36.1, 56.3, 60.9,
61.1, 88.1, 109.3, 114.4, 120.3, 126.3, 130.6, 131.1, 138.2, 140.9,
146.3, 153.4, 153.8, 171.4 ppm. IR (ATR): ν = 751, 771, 782, 924,
˜
959, 1004, 1034, 1074, 1104, 1166, 1199, 1238, 1288, 1327, 1387
(strong), 1450, 1482, 1564, 1737 (strong), 2847, 2937, 2966 cm–1.
MS (EI, 70 eV): m/z (%) = 165 (33), 179 (27), 193 (20), 207 (60),
221 (19), 237 (10), 251 (12), 254 (18), 266 (60), 282 (37), 291 (13),
307 (48), 312 (30), 320 (100), 467 (80) [M]+. C18H18IN3O4 (467.26):
calcd. C 46.27, H 3.88, N 8.99; found C 46.21, H 3.87, N 9.02.
1
1:1), m.p. 185 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.05 (s,
1 H, OH), 2.62–2.75 (m, 1 H, CH2), 2.81–2.94 (m, 2 H, CH2), 3.26–
3.40 (m, 1 H, CH2), 3.45 (s, 3 H, CH3), 3.68 (s, 3 H, CH3), 3.93 (s,
6 H, CH3), 6.69 (s, 1 H, 4Ј-H), 7.20–7.25 (m, 1 H, ArH), 7.28–7.34
(m, 1 H, ArH), 7.41 (d, 3J = 8.1 Hz, 1 H, 7ЈЈ-H), 8.05 (d, 3J =
7.7 Hz, 1 H, 4ЈЈ-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
31.1, 32.4, 34.4, 56.3, 61.0, 61.6, 108.2, 109.7, 110.2, 116.4, 120.8,
121.0, 122.6, 125.8, 136.1, 137.9, 138.4, 141.2, 151.9, 153.8,
3-(2Ј-Iodo-3Ј,4Ј,5Ј-trimethoxyphenyl)-1-(1ЈЈ-methyl-1H-indol-3ЈЈ-
yl)propan-1-one (12): Titanium tetrachloride (215 μL, 2.0 mmol)
was added to a solution of 38 (482 mg, 1.0 mmol) and 1-methyl-
1H-indole (158 μL, 1.25 mmol) in CH2Cl2 (10 mL) under an argon
atmosphere. The reaction mixture was stirred for 4 h at room temp.
followed by quenching with MeOH (1 mL) and evaporation of the
solvent under reduced pressure. After column chromatography on
silica gel (eluent petroleum ether/EtOAc, 1:1) compound 12
(239 mg, 50%) was obtained as a white polycrystalline powder. Rf
= 0.49 (petroleum ether/EtOAc, 1:1), m.p. 153 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 3.10–3.16 [m, 2 H, CH2C(O)], 3.18–
3.25 (m, 2 H, CH2Ar), 3.79 (s, 3 H, NCH3), 3.82 (s, 3 H, OCH3),
3.83 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 6.76 (s, 1 H, 6Ј-H), 7.29–
7.35 (m, 3 H, 5ЈЈ-H, 6ЈЈ-H, 7ЈЈ-H), 7.75 (s, 1 H, 2ЈЈ-H), 8.38–8.44
(m, 1 H, 4ЈЈ-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
33.7, 36.6, 40.3, 56.3, 60.9, 61.1, 87.8, 109.5, 109.7, 116.6, 122.7,
122.8, 123.5, 126.4, 135.7, 137.6, 140.2, 140.5, 153.2, 153.7,
157.0 ppm. IR (ATR): ν = 742, 909, 977, 981, 1017, 1095, 1196,
˜
1313, 1320, 1392, 1425, 1456, 1464, 1490, 1559, 1592, 1599, 1739,
2843, 2934, 3450 cm–1. MS (EI, 70 eV): m/z (%) = 183 (7), 319 (14),
349 (13), 366 (100) [M]+. C21H22N2O4 (366.41): calcd. C 68.84, H
6.05, N 7.65; found C 69.02, H 6.07, N 7.63.
1Ј,2Ј,3Ј-Trimethoxybenzo[5Ј,6Ј:5,4]-1-acetamido-6,7-dihydro-1H-
cyclohepta[3,2-b]-1ЈЈ-methyl-1H-indole (rac-10): Oxime 40 (107 mg,
0.292 mmol) was dissolved in absolute MeOH (5 mL) under an ar-
gon atmosphere at 50 °C. The solution was then slowly cooled to
room temp. and NiCl2 (75 mg, 0.585 mmol) and NaBH4 (66 mg,
1.752 mmol) were sequentially added (caution: vigorous hydrogen
evolution). The reaction mixture was stirred at room temp. for 12 h
and a new portion of NiCl2 (38 mg, 0.292 mmol) and NaBH4
(11 mg, 0.292 mmol) was added after each 2 h. The reaction mix-
ture was then diluted with EtOAc (20 mL), the resulting suspension
filtered through Celite® and the volatiles were removed under re-
duced pressure. After column chromatography on silica gel (eluent
EtOAc/EtOH/Et3N, 10:1:0.2) the corresponding amine (41 mg,
194.2 ppm. IR (ATR): ν = 747, 925, 1007, 1089, 1103, 1126, 1164,
˜
1200, 1249, 1271, 1328, 1337, 1374, 1387, 1425, 1464, 1479, 1530,
1560, 1577, 1642, 2849, 2918, 2958, 3380 (strong) cm–1. MS (EI,
70 eV): m/z (%) = 158 (51), 352 (100), 479 (1) [M]+. C21H22INO4
(479.31): calcd. C 52.62, H 4.63, N 2.92; found C 52.69, H 4.64, N
2.92.
1Ј,2Ј,3Ј-Trimethoxybenzo[5Ј,6Ј:5,4]-6,7-dihydro-1-oxo-1H-cyclo-
hepta-[3,2-b]-1ЈЈ-methyl-1H-indole (39): The reaction was carried 40%) was obtained as a pale-brown solid. Rf = 0.25 (EtOAc/EtOH/
1
out in a glass vial (10 bar pressure limit) equipped with a mininert®
Et3N, 10:1:0.2). H NMR (400 MHz, CD3OD, 25 °C) (ca. 1:1 mix-
Teflon® valve. Compound 12 (100 mg, 0.209 mmol), Pd(OAc)2
ture of conformers): δ = 1.96–2.06 (m, 1 H, CH2), 2.07–2.16 (m, 1
(4.7 mg, 0.02 mmol), pivalic acid (53 mg, 0.523 mmol) and Cs2CO3 H, CH2), 2.22–2.32 (m, 1 H, CH2), 2.41–2.58 (m, 4 H, CH2), 2.59–
(204 mg, 0.627 mmol) were dissolved in anhydrous degassed DMF
(2 mL) under an argon atmosphere and the reaction mixture was
stirred at 110 °C for 24 h. The resulting suspension was cooled to
room temp., diluted with EtOAc (20 mL), and filtered through Ce-
lite® before evaporation of all volatiles under reduced pressure. Af-
ter column chromatography on silica gel (eluent petroleum ether/
EtOAc, 3:2) compound 39 (53 mg, 76%) was obtained as a pale-
2.68 (m, 1 H, CH2), 3.46 (s, 3 H, CH3), 3.52 (s, 3 H, CH3), 3.61 (s,
3 H, CH3), 3.62 (s, 3 H, CH3), 3.87–3.93 (m, 1 H, 1-H), 3.87 (s, 3
H, CH3), 3.88 (s, 3 H, CH3), 3.89 (s, 3 H, CH3), 3.90 (s, 3 H, CH3),
3
4.53 (dd, 3J = 8.3, J = 2.2 Hz, 1 H, 1-H), 6.83 (s, 1 H, ArH), 6.87
(s, 1 H, ArH), 7.01–7.10 (m, 2 H, ArH), 7.12–7.20 (m, 2 H, ArH),
3
7.35–7.40 (m, 2 H, ArH), 7.58 (d, J = 7.9 Hz, 1 H, ArH), 7.95 (d,
3J = 8.1 Hz, 1 H, ArH) ppm. 13C NMR (400 MHz, CD3OD, 25 °C)
yellow solid. Rf = 0.41 (petroleum ether/EtOAc, 1:1), m.p. 172 °C. (ca. 1:1 mixture of conformers): δ = 31.8, 31.9, 32.7, 33.2, 43.9,
6490
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6481–6492