Organic & Biomolecular Chemistry
Paper
(45 mg, 0.25 mmol, 1.2 eq.) were suspended in dry dimethoxy- (CDCl3): δ (ppm) = 1.38 (d, 6.2 Hz, 6H, CH(CH3)2), 1.52–1.87
ethane (8 mL). The crude product was purified by fc (EtOAc– (m, 4H, 3-CH2pyran, 5-CH2pyran), 2.07–2.20 (m, 2H, 6-CH2), 2.21
MeOH = 95 : 5) and recrystallized from acetonitrile to give 9f as (s, 3H, N–CH3), 2.58–2.69 (m, 1H, 4-CHpyran), 2.72 (t, J = 6.6 Hz,
a
colorless solid. (Rf = 0.22, CH2Cl2–MeOH = 95 : 5), 2H, 7-CH2), 2.81–2.98 (m, 2H, 5-CH2), 3.37 (td, J = 11.6/2.3 Hz,
mp 164–165 °C, yield 88 mg (79%). C35H42N2O2 (522.7 g 2H, CH2axial–O–CH2axial), 3.57 (s, 2H, Ph–CH2–N), 4.04 (dd, J =
mol−1). HRMS (APCI): m/z = calcd for C35H43N2O2 [MH+] 11.5/4.3 Hz, 2H, CH2equat–O–CH2equat), 5.34 (sept. J = 6.2 Hz,
523.3319, found 523.3335. 1H NMR (CDCl3): δ (ppm) = 1.36 1H, CH(CH3)2), 6.75 (d, J = 8.6 Hz, 1H, 5-CHpyridine), 7.24 (d, J =
(s, 9H, 2-CH3butyl, 3-CH3butyl, 4-CH3butyl), 1.62–1.84 (m, 4H, 8.1 Hz, 1H, 4-CH), 7.31 (d, J = 8.2 Hz, 2H, 3-CHphenyl
3-CH2pyran, 5-CH2pyran), 2.17 (t, J = 5.9 Hz, 2H, 6-CH2), 2.21 5-CHphenyl), 7.37 (dd, J = 7.9/1.8 Hz, 1H, 3-CH), 7.40 (s, 1H,
(s, 3H, N-CH3), 2.51–2.69 (m, 1H, 4-CHpyran), 2.72 (t, J = 6.6 Hz, 9-CH), 7.44 (s, 1H, 1-CH), 7.56 (d, J = 8.4 Hz, 2H, 2-Hphenyl
,
,
2H, 7-CH2), 2.84–2.94 (m, 2H, 5-CH2), 3.37 (td, J = 11.5/2.3 Hz, 6-Hphenyl), 7.64 (s, 1H, N–H), 7.75 (dd, J = 8.6/2.6 Hz, 1H,
2H, CH2axial–O–CH2axial), 3.57 (s, 2H, Ph–CH2–N), 4.04 (dd, 4-CHpyridine), 8.35 (d, J = 2.6 Hz, 1H, 2-CHpyridine).
J = 10.9/4.1 Hz, 2H, CH2equat–O–CH2equat), 7.23 (d, J = 7.8, 1H,
2-(4-Methylphenyl)-N-{4-[N-methyl-N-(tetrahydro-2H-pyran-4-
4-CH), 7.31 (d, J = 8.4 Hz, 2H, 3-CHphenyl, 5-CHphenyl), 7.41–7.44
yl)aminomethyl]phenyl}-7,8-dihydro-6H-[7]annuleno[b]-
(m, 2H, 9-CH, 3-CH), 7.47 (d, J = 8.4 Hz, 2H, 3-CHbutylphenyl
5-CHbutylphenyl), 7.51–7.54 (m, 3H, 1-CH, 2-CHbutylphenyl.
6-CHbutylphenyl), 7.56 (d, J = 8.5 Hz, 2H, 2-Hphenyl, 6-Hphenyl), N-(4-Aminophenyl)-N-methyltetrahydro-2H-pyran-4-amin
,
thiophene-5-carboxamide (14a)
7.62 (s, 1H, N–H).
(78 mg, 0.35 mmol, 1 eq.) was added to a vigorously stirred
mixture of acid 13a40 (100 mg, 0.35 mmol), triethylamine
(71 mg, 0.70 mmol, 2 eq.) and HATU™ (150 mg, 0.38 mmol.
1.1 eq.) in THF (5 mL). The mixture was stirred overnight at rt.
The mixture was concentrated in vacuo and the residue was
N-{4-[N-Methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]-
phenyl}-2-(naphtalen-2-yl)-6,7-dihydro-5H-benzo[7]annulene-
8-carboxamide (9h)
According to general procedure
A amide 7 (100 mg, purified by fc (EtOAc–CH2Cl2 = 1 : 2 + 5% MeOH) and recrystal-
0.21 mmol), PdCl2(dppf) (8 mg, 0.01 mmol, 5 mol%), KOAc lized from acetonitrile to give 14a as a yellow solid. Rf = 0.13
(40 mg, 0.42 mmol, 2 eq.) and 2-naphthylboronic acid (40 mg, (MeOH–CH2Cl2 = 5 : 95), mp 201 °C, yield 136 mg (80%).
0.23 mmol, 1.1 eq.) were suspended in dry dimethoxyethane C30H34N2O2S (486.6 g mol−1). HRMS (APCI): m/z = calcd for
(5 mL).). The crude product was purified by fc (EtOAc–MeOH = C30H35N2O2S [MH+] 487.2414, found 487.2381. 1H NMR
95 : 5) and recrystallized from acetonitrile to give 9h as a color- (CDCl3): δ (ppm) = 1.55–1.83 (m, 4H, 3-CH2pyran, 5-CH2pyran),
less solid. Rf = 0.19, CH2Cl2–MeOH = 95 : 5), mp 172–174 °C, 2.13 (quint, J = 5.1 Hz, 2H, 7-CH2), 2.21 (s, 3H, N-CH3), 2.36 (s,
yield 84 mg (77%). C35H36N2O2 (516.6 g mol−1). HRMS (APCI): 3H, CH3tolyl), 2.64 (tt, J = 10.9/3.5 Hz, 1H, 4-Hpyran), 2.84 (t, J =
m/z = calcd for C35H37N2O2 [MH+] 517.2850, found 517.2880. 5.8 Hz, 2H, 6-CH2), 3.11 (t, J = 5.6 Hz, 2H, 8-CH2), 3.37 (td, J =
1H NMR (CDCl3): δ (ppm) = 1.63–1.88 (m, 4H, 3-CH2pyran
,
11.6/2.3 Hz, 2H, CH2axial–O–CH2axial), 3.57 (s, 2H, Ph–CH2–N),
5-CH2pyran), 2.15–2.20 (m, 2H, 6-CH2), 2.21 (s, 3H, N-CH3), 2.64 4.04 (dd, J = 11.4/4.4 Hz, 2H, CH2equat–O–CH2equat), 7.07 (s, 1H,
(tt, J = 11.1/4.1 Hz, 1H, 4-CHpyran), 2.75 (t, J = 6.6 Hz, 2H, 3-CH), 7.14–7.24 (m, 3H, 3-CHtolyl, 5-CHtolyl, 4-CH), 7.30 (d, J =
7-CH2), 2.87–2.97 (m, 2H, 5-CH2), 3.37 (td, J = 11.6/2.4 Hz, 2H, 8.2 Hz, 2H, 3-CHphenyl, 5-CHphenyl), 7.42 (d, J = 8.1 Hz, 2H,
CH2axial–O–CH2axial), 3.57 (s, 2H, Ph–CH2–N), 4.04 (dd, J = 2-CHtolyl, 6-CHtolyl), 7.49–7.57 (m, 3H, 2-CHphenyl, 6-CHphenyl
10.8/4.3 Hz, 2H, CH2equat–O–CH2equat), 7.28–7.37 (m, 3H, 4-CH, NH).
,
3-CHphenyl, 5-CHphenyl), 7.45–7.54 (m, 3H, 9-CH, 6,7-CHnaphthyl),
2-(4-Methylphenyl)-N-[2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-
7.55–7.61 (m, 3H, 3-CH, 2-CHphenyl, 6-CHphenyl), 7.63 (s, 1H,
tetrahydroisoquinolin-7-yl]-7,8-dihydro-6H-[7]annuleno[b]-
thiophene-5-carboxamide (14b)
N–H), 7.68 (d, J = 2.0 Hz, 1H, 1-CH,), 7.74 (dd, J = 8.5/1.9 Hz,
1H, 3-CHnaphtyl), 7.82–7.98 (m, 3H, 1-CHnaphthyl, 5,8-CHnaphthyl),
8.04 (d, J = 1.8 Hz, 1H, 4-CHnaphthyl).
2-(Tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-
amine (82 mg, 0.35 mmol, 1 eq.) was added to a vigorously
stirred mixture of acid 13a40 (100 mg, 0.35 mmol), triethyl-
amine (71 mg, 0.70 mmol, 2 eq.) and HATU™ (150 mg,
0.38 mmol. 1.1 eq.) in THF (5 mL). The mixture was stirred
2-(6-Isopropoxypyridin-3-yl)-N-{4-[N-methyl-N-(tetrahydro-2H-
pyran-4-yl)aminomethyl]phenyl}-6,7-dihydro-5H-benzo[7]-
annulene-8-carboxamide (9k)
According to general procedure
A amide 7 (172 mg, overnight at rt. The mixture was concentrated in vacuo and the
0.37 mmol), PdCl2(dppf) (15 mg, 0.02 mmol, 5 mol%), KOAc residue was purified by fc (EtOAc–CH2Cl2 = 1 : 2 + 5% MeOH))
(73 mg, 0.74 mmol, 2 eq.) and 6-isopropoxypyridine-3-ylboro- and recrystallized from acetonitrile to give 14b as a yellow
nic acid (100 mg, 0.55 mmol, 1.5 eq.) were suspended in dry solid. Rf = 0.34 (MeOH–CH2Cl2 = 5 : 95), mp 215 °C (dec.), yield
dimethoxyethane (10 mL). The crude product was purified by 120 mg (69%). C31H34N2O2S (498.6 g mol−1). HRMS (APCI):
fc (CH2Cl2–EtOAc + 5% MeOH = 2 : 1) and recrystallized from m/z = calcd for C31H35N2O2S [MH+] 499.2414, found 499.2389.
acetonitrile to give 9k as a colorless solid. Rf = 0.06 (CH2Cl2– 1H NMR (CDCl3): δ (ppm) = 1.69 (dq, J = 12.1/4.2 Hz,
EtOAc + 5% MeOH = 2 : 1), mp 173–175 °C, yield 132 mg 2H, 3-CH2pyran-equat
,
5-CH2pyran-equat), 1.81–1.90 (m, 2H,
(67%). C33H39N3O3 (525.7 g mol−1). HRMS (APCI): m/z = calcd 3-CH2pyran-axial, 5-CH2pyran-axial), 2.11 (quint, J = 5.9 Hz, 2H,
for C33H40N3O3 [MH+] 526.3064, found 526.3077. 1H NMR 7-CH2), 2.36 (s, 3H, CH3tolyl), 2.65 (tt, J = 11.1/3.8 Hz, 1H,
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