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(57.0 mg, 0.38 mmol, 1.0 equiv) was added. The reaction mixture
was stirred for 16 h at RT. Water (100 mL) was added and after ex-
traction with ethyl acetate (5ꢄ10 mL), the organic layer was dried
(Na2SO4) and concentrated in vacuo. The crude product was puri-
fied by FC (d=2 cm, l=21 cm, v=7 mL, CH2Cl2/CH3OH=98:2+1%
HCOOH). Pale-beige solid, mp: 1848C (dec.), yield 13.5 mg
(0.04 mmol, 10%). C18H16FN3O4 (357.3). Rf =0.50 (CH2Cl2/CH3OH=
95:5). 1H NMR (400 MHz, [D6]DMSO): d=2.85–3.05 (m, 2H,
PhCH2CHFCH2NH), 3.37–3.57 (m, 2H, PhCH2CHFCH2NH), 4.80–4.98
(dm, J=49.3 Hz, 1H, CHF), 7.06 (d, J=8.5 Hz, 1H, 4-H), 7.21–7.34
(m, 5H, 2-Hphenyl, 3-Hphenyl, 4-Hphenyl, 5-Hphenyl, 6-Hphenyl), 7.60 (dd, J=
8.5/1.9 Hz, 1H, 5-H), 7.81 (d, J=1.9 Hz, 1H, 7-H), 9.11 (t, J=6.0 Hz,
1H, CH2NHCOCONH), 10.73 (s, 1H, CH2NHCOCONH), 11.61 ppm
(1H, NH); 13C NMR (101 MHz, [D6]DMSO): d=38.4 (d, J=20.7 Hz,
1C, PhCH2CHFCH2NH), 42.8 (d, J=23.0 Hz, 1C, PhCH2CHFCH2NH),
92.1 (d, J=173.1 Hz, 1C, CHF), 102.6 (1C, C-7), 109.4 (1C, C-4), 116.1
(1C, C-5), 126.5 (1C, C-4phenyl), 127.1 (1C, C-3a), 128.3 (2C, C-3phenyl, C-
cyclohexane/ethyl acetate=1:1; 2. d=2 cm, l=26 cm, v=7 mL,
CH2Cl2/CH3OH=98:2). Pale-yellow solid, mp: 1838C, yield 54.3 mg
(0.17 mmol, 39%). C18H17FN2O2 (312.3). Rf =0.36 (cyclohexane/ethyl
acetate=1:1). 1H NMR (400 MHz, CD3OD): d=2.91–3.06 (m, 2H,
NHCH2CHFCH2Ph),
NHCH2CHFCH2Ph),
NHCH2CHFCH2Ph),
3.53
3.68
4.76–4.94
(ddd,
(ddd,
J=17.7/14.4/7.4 Hz,
J=27.3/14.4/3.5 Hz,
1H,
1H,
1H,
(dm,
J=49.9 Hz,
NHCH2CHFCH2Ph), 6.81 (dd, J=8.6/2.2 Hz, 1H, 5-H), 6.79–6.81 (m,
1H, 7-H), 7.01 (d, J=0.9 Hz, 1H, 3-H), 7.19–7.32 (m, 5H, 2-Hphenyl, 3-
Hphenyl, 4-Hphenyl, 5-Hphenyl, 6-Hphenyl), 7.41 ppm (dd, J=8.7/0.5 Hz, 1H,
4-H). Signals for the OH and NH protons are not observed in the
spectrum. 13C NMR (101 MHz, CD3OD): d=40.2 (d, J=20.9 Hz, 1C,
NHCH2CHFCH2Ph), 44.2 (d, J=22.6 Hz, 1C, NHCH2CHFCH2Ph), 94.1
(d, J=173.9 Hz, 1C, NHCH2CHFCH2Ph), 97.4 (1C, C-7), 105.3 (1C, C-
3), 112.5 (1C, C-5), 122.9 (1C, C-3a), 123.5 (1C, C-4), 127.6 (1C, C-
4phenyl), 129.4 (2C, C-3phenyl, C-5phenyl), 130.45 (2C, C-2phenyl, C-6phenyl),
130.51 (1C, C-2), 138.3 (d, J=3.5 Hz, 1C, C-1phenyl), 139.7 (1C, C-7a),
156.5 (1C, C-6), 164.5 ppm (1C, CONH); 19F NMR (376 MHz, CDCl3):
d=ꢀ184.1 ppm (m, 1F); HRMS (APCI): m/z=313.1361 (calcd
313.1347 for C18H18FN2O2 [M+H]+); Purity (HPLC): 95.2%, tR =
18.2 min. IR: n˜ =3414 (NꢀH), 3279 (OꢀH), 1620 (C=O), 1547,
1508 cmꢀ1 (C=Carom.).
5
phenyl), 129.3 (2C, C-2phenyl, C-6phenyl), 132.2 (1C, C-6), 136.8 (d, J=
3.7 Hz, 1C, C-1phenyl), 143.0 (1C, C-7a), 154.6 (1C, C-2), 158.1 (1C,
CH2NHCOCO), 160.3 ppm (1C, CH2NHCOCO); 19F NMR (376 MHz,
CDCl3): d=ꢀ183.4 ppm (m, 1F); HRMS (APCI): m/z=258.1190
(calcd 258.1198 for C18H17FN3O4 [M+H]+); Purity (HPLC): 94.3%,
tR =18.2 min. IR: n˜ =3275 (NꢀH), 2920 (CꢀHaliph.), 1763, 1732, 1655
(C=O), 1582, 1520 (C=Carom.), 745, 698 cmꢀ1 (monosubst. arom.).
N-(3-Fluoro-4-phenylbutyl)-6,7,8,9-tetrahydro-5H-benzo[7]annu-
len-7-amine (12c): A solution of ketone 39 (144 mg, 0.90 mmol,
1.0 equiv), amine 7c (150 mg, 0.90 mmol, 1.0 equiv) and NaB-
H(OAc)3 (381 mg, 1.80 mmol, 2.0 equiv) in CH2Cl2 (8 mL) was stirred
overnight at RT. Afterward, a saturated solution of NaHCO3 (15 mL)
was added, the organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3ꢄ10 mL). The combined organic layers
were dried (Na2SO4), filtered and concentrated in vacuo. The crude
product was purified by FC (d=2 cm, l=24 cm, v=7 mL, CH2Cl2/
CH3OH=99:1+1% N,N-dimethylethanamine). Pale-yellow oil, yield
220 mg (0.71 mmol, 79%). C21H26FN (311.4). Rf =0.24 (CH2Cl2/
CH3OH=98:2+1% N,N-dimethylethanamine). 1H NMR (600 MHz,
CDCl3): d=1.24–1.28 (m, 2H, 6-H, 8-H), 1.74–1.94 (m, 2H,
NHCH2CH2CHFCH2Ph), 2.06–2.15 (m, 2H, 6-H, 8-H), 2.67–3.02 (m,
9H, 2ꢄ5-H, 7-H, 2ꢄ9-H, NHCH2CH2CHFCH2Ph), 4.76–4.88 (dm, J=
48.9 Hz, 1H, CHF), 7.08–7.11 (m, 4H, 1-H, 2-H, 3-H, 4-H), 7.21–7.26
3-(Methoxymethyl)-6-{3-[(3-phenylpropyl)amino]prop-1-yn-1-yl}-
benzoxazol-2-one (9e): Aryl bromide 27b (80.0 mg, 0.31 mmol,
1.0 equiv) was dissolved in Et3N (4 mL) and THF (1 mL). CuI
(8.9 mg, 0.05 mmol, 0.15 equiv), Pd(PPh3)4 (35.8 mg, 0.03 mmol,
0.10 equiv) and alkyne 31c (107 mg, 0.62 mmol, 2.0 equiv) were
added and the solution was heated at reflux for 15 h. The solvent
was removed in vacuo and the residue was purified by FC (d=
2 cm, l=28 cm, v=7 mL, cyclohexane/ethyl acetate=6:4 + 1%
N,N-dimethylethanamine). Yellow oil, yield 89.9 mg (0.26 mmol,
83%). C21H22N2O3 (350.4). Rf =0.22 (cyclohexane/ethyl acetate=6:4
1
+ 1% N,N-dimethylethanamine). H NMR (600 MHz, CDCl3): d=1.88
(quint, J=7.1 Hz, 2H, NHCH2CH2CH2Ph), 2.71 (t, J=7.5 Hz, 2H,
NHCH2CH2CH2Ph), 2.80 (t, J=6.8 Hz, 2H, NHCH2CH2CH2Ph), 3.40 (s,
3H, NCH2OCH3), 3.66 (d, J=4.7 Hz, 2H, CCCH2NH), 5.23 (s, 2H,
(m, 3H, 2-Hphenyl, 4-Hphenyl, 6-Hphenyl), 7.29–7.32 ppm (m, 2H, 3-Hphenyl
,
NCH2OCH3), 7.06 (d, J=8.0 Hz, 1H, 4-H), 7.17–7.22 (m, 3H, 2-Hphenyl
,
5-Hphenyl). A signal for the NH proton is not observed in the spec-
trum. 13C NMR (151 MHz, CDCl3): d=32.3 (2C, C-5, C-9), 34.1 (1C, C-
4-Hphenyl, 6-Hphenyl), 7.24–7.29 ppm (m, 4H, 5-H, 7-H, 3-Hphenyl, 5-
Hphenyl). A signal for the NH proton is not observed in the spectrum.
13C NMR (151 MHz, CDCl3): d=31.5 (1C, NHCH2CH2CH2Ph), 33.7 (1C,
NHCH2CH2CH2Ph), 39.1 (1C, CCCH2NH), 48.3 (1C, NHCH2CH2CH2Ph),
57.0 (1C, NCH2OCH3), 74.2 (1C, NCH2OCH3), 82.8 (1C, CCCH2NH),
87.6 (1C, CCCH2NH), 109.3 (1C, C-4), 113.4 (1C, C-7), 118.5 (1C, C-6),
126.0 (1C, C-4phenyl), 128.3 (1C, C-5), 128.52 (2C, C-3phenyl, C-5phenyl),
128.54 (2C, C-2phenyl, C-6phenyl), 130.1 (1C, C-3a), 142.1 (1C, C-1phenyl),
142.4 (1C, C-7a), 154.5 ppm (1C, C-2); HRMS (APCI): m/z=351.1673
(calcd 351.1703 for C21H23N2O3 [M+H]+); Purity (HPLC): 92.6%, tR =
17.0 min. IR: n˜ =3024 (CꢀHaryl), 2932 (CꢀHaliph.), 2291 (CꢂC), 1778
(C=O), 1605, 1493 (C=Carom.), 1443 (CꢀHaliph.), 748, 694 cmꢀ1 (mono-
subst. arom.).
6
or C-8), 34.3 (1C, C-6 or C-8), 35.3 (d, J=19.5 Hz, 1C,
NHCH2CH2CHFCH2Ph), 41.9 (d, J=21.4 Hz, 1C,
NHCH2CH2CHFCH2Ph), 43.0 (d, J=3.8 Hz, 1C, NHCH2CH2CHFCH2Ph),
61.5 (1C, C-7), 93.3 (d, J=170.7 Hz, 1C, CHF), 126.4 (2C, C-2, C-3),
126.8 (1C, C-4phenyl), 128.6 (2C, C-3phenyl, C-5phenyl), 129.0 (2C, C-1, C-
4), 129.5 (2C, C-2phenyl, C-6phenyl), 137.15 (d, J=4.8 Hz, 1C, C-1phenyl),
142.46 (1C, C-4a or C-9a), 142.49 ppm (1C, C-4a or C-9a). Ratio of
diastereomers is approximately 1:1. 19F NMR (376 MHz, CDCl3): d=
ꢀ180.2 ppm (m, 1F). HRMS (APCI): m/z=312.2131 (calcd 312.2122
for C21H27FN [M+H]+). Purity (HPLC): 99.2%, tR =19.2 min. IR: n˜ =
3021 (CꢀHaryl), 2928 (CꢀHaliph.), 1493 (NHdeform.), 1451 (CꢀHaliph.), 741,
698 cmꢀ1 (monosubst. arom.).
N-(2-Fluoro-3-phenylpropyl)-6-hydroxy-1H-indole-2-carboxamide
(11a): 4-DMAP (138 mg, 1.13 mmol, 2.5 equiv) and EDC·HCl
(173 mg, 0.90 mmol, 2.0 equiv) were added to a solution of acid 38
(80.0 mg, 0.45 mmol, 1.0 equiv) and amine 7a (69.3 mg, 0.45 mmol,
1.0 equiv) in DMF (3 mL). The mixture was stirred for 18 h at RT.
Water (50 mL) and ethyl acetate (10 mL) were added, the layers
were separated and the aqueous layer was extracted with ethyl
acetate (3ꢄ10 mL). The combined organic layers were dried
(Na2SO4), filtered and the solvent was removed in vacuo. The crude
product was purified by FC twice (1. d=2 cm, l=19 cm, v=7 mL,
3-(2-Fluoro-4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine
(13a): A mixture of 2,3,4,5-tetrahydro-1H-3-benzazepine (255 mg,
1.73 mmol, 1.0 equiv), an excess of freshly prepared crude alde-
hyde 7d and NaBH(OAc)3 (734 mg, 3.46 mmol, 2.0 equiv) in CH2Cl2
(15 mL) was stirred for 20 h at RT. A saturated solution of NaHCO3
(20 mL) was added, the organic layer was separated and the aque-
ous layer was extracted with CH2Cl2 (3ꢄ15 mL). The combined or-
ganic layers were dried (Na2SO4), filtered and concentrated in
vacuo. The crude product was purified by FC twice (1. d=3 cm, l=
ChemMedChem 2018, 13, 1 – 9
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