MedChemComm
Research Article
(1C, C-4ar), 128.6 (2C, C-2ar, C-6ar), 128.7 (2C, C-3ar, C-5ar),
140.7 (1C, C-1ar). 19F NMR (CDCl3): δ (ppm) = −179.95. FT-
IR (neat): ν [cm−1] = 3063 (CH2–Br), 2951, 2928, 2862 (C–
1ar). 19F NMR (CDCl3): δ (ppm) = −186.1. FT-IR (neat): ν
[cm−1] = 3028 (Aryl-H), 2928 (C–Halkyl), 2095 (–N3), 1601, 1586,
1497 (C–Harom).
H
alkyl), 1601, 1586, 1497 (C–Harom).
5.2.7. 2-Fluoro-3-phenylpropan-2-amine (14a). A mixture of
13a (89.6 mg, 0.50 mmol), Pd/C (10% w/w, 50 mg) and CH3-
OH (4 mL) was stirred under H2 (balloon) at rt for 4 h. The
suspension was filtered over Celite® and the filtrate was con-
centrated in vacuo. Colorless solid, yield 71.5 mg (86%).
C9H12FN (153.2). Since the purity of compound 14a was very
high, it was used for the reductive amination of ketone 6
without further purification.
5.2.4. 1-Azido-3-phenylpropan-2-ol (12a)24. A solution of
oxirane 11a (670 mg, 5.6 mmol), NaN3 (975 mg, 15 mmol)
and NH4Cl (401 mg, 7.5 mmol) in H2O (3 mL) and CH3OH
(15 mL) was heated to reflux for 1 h. Ethyl acetate (50 mL)
and H2O (50 mL) were added, the organic layer was separated
and the aqueous layer was extracted with ethyl acetate (3 × 50
mL). The combined organic layers were washed with brine
(50 mL), dried (Na2SO4), filtered, concentrated in vacuo and
the residue was purified by fc (4 cm, cyclohexane/ethyl ace-
tate = 1 : 1, 20 mL, Rf = 0.25). Colorless oil, yield 782 mg
(79%). C9H11N3O (177.2). Purity (HPLC): 87%, tR = 17.4 min.
Exact MS (APCI): m/z = calcd. for C9H12NO [MH+ − N2]
150.0913, found 150.914. 1H NMR (CDCl3): δ (ppm) = 2.71–
2.84 (m, 2H, CH2N3), 3.24 (dd, J = 12/6.8 Hz, 1H, CH2Ph),
3.32 (dd, J = 12/6.8 Hz, 1H, CH2Ph), 3.90–3.97 (m, 1H,
CHOH), 7.14–7.21 (m, 3H, arom.), 7.23–7.28 (m, 2H, arom.).
FT-IR (neat): ν [cm−1] = 3395 (O–H), 2099 (–N3), 1601, 1586,
1493 (C–Harom), 1080 (C–O).
5.2.5. (3-Azido-2-fluoropropyl)benzene (13a). At −78 °C, a
solution of DAST (806 mg, 5.0 mmol) in CH2Cl2 (5 mL) was
added to a solution of 12a (709 mg, 4.0 mmol) in CH2Cl2 (5
mL). The cooling bath was removed and the mixture was
stirred for 3 h. H2O (10 mL) was added and the mixture was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried (Na2SO4), filtered, concentrated in vacuo
and the residue was purified by fc (4 cm, hexane/ethyl acetate
= 10 : 1, 20 mL, Rf = 0.18). Colorless oil, yield 213 mg (30%).
C9H10FN3 (179.2). Purity (HPLC): 86%, tR = 21.7 min. Exact
MS (APCI): m/z = calcd. for C9H11FN [MH − N2] 152.0876,
found 152.0857. 1H NMR (CDCl3): δ (ppm) = 2.83–3.05 (m,
2H, CH2N3), 3.25–3.39 (m, 2H, CH2Ph), 4.67–4.86 (m, 1H,
CHF), 7.13–7.27 (m, 5H, arom.), 19F NMR (CDCl3): δ (ppm) =
−182.1. FT-IR (neat): ν [cm−1] = 3028 (Aryl-H), 2936 (C–Halkyl),
2099 (–N3), 1605, 1585, 1497 (C–Harom).
5.2.8. 2-Fluoro-4-phenylbutan-1-amine (14b). A mixture of
13b (2640 mg, 13.7 mmol), PdIJOH)2/C (20% w/w, 270 mg), 1
M HCl (12 mL) and CH3OH (30 mL) was stirred under H2
(balloon) at rt for 7 h. The suspension was filtered over
Celite® and the filtrate was concentrated in vacuo. The prod-
uct was purified by fc (6 cm, l = 12 cm, CH2Cl2/CH3OH/Et3N =
93.5 : 5 : 1.5, 60 mL, Rf = 0.17). Colorless oil, yield 1165 mg
(51%). C10H15FN (167.2). Purity (HPLC): 99%, tR = 13.1 min.
Exact MS (APCI): m/z = calcd. for C10H15FN [MH+] 168.1183,
found 168.1172. 1H NMR (CDCl3): δ (ppm) = 1.76–2.04 (m,
2H, CH2CH2Ph), 2.68–2.73 (m, 1H, CH2Ph), 2.80–2.90 (m, 3H,
CH2Ph, CH2NH2), 4.39–4.51 (m, 1H, CHF), 7.18–7.22 (m, 3H,
2-CHar, 4-CHar, 6-CHar), 7.28–7.31 (m, 2H, 3-CHar, 5-CHar). 13C
NMR (CDCl3): δ (ppm) = 31.4 (d, 1C, J = 4.4 Hz, CH2Ph), 34.3
(d, 1C, J = 20.7 Hz, CH2CH2Ph), 46.4 (d, 1C, J = 21.7 Hz,
CH2NH2), 94.9 (d, 1C, J = 168.5 Hz, CHF), 126.2 (1C, C-4ar),
128.57 (2C, C-2ar, C-6ar), 128.61 (2C, C-3ar, C-5ar), 141.3 (1C,
C-1ar). 19F NMR (CDCl3): δ (ppm) = −190.2. FT-IR (neat): ν
+
[cm−1] = 3028 (Aryl-H), 3001 (NH3 ), 2955, 2920 (C–Halkyl),
1597, 1512, 1497 (C–Harom).
5.2.9. N-(2-Fluoro-3-phenylpropyl)-6,7,8,9-tetrahydro-5H-
benzoij7]annulen-7-amine (5a). A mixture of ketone 6 (64.1
mg, 0.40 mmol), primary amine 14a (65.9 mg, 0.43 mmol),
NaBHIJOAc)3 (424 mg, 2.0 mmol) and CH2Cl2 (14 mL) was
stirred at rt for 24 h. Saturated NH4Cl solution (10 mL) was
added and the mixture was extracted with CH2Cl2 (3 × 30
mL). The combined organic layers were dried (Na2SO4), fil-
tered, concentrated in vacuo and the residue was purified by
fc (2 cm, CH2Cl2/CH3OH/Et3N = 200 : 1 : 1, 7 mL, Rf = 0.22)
and preparative tlc (CH2Cl2/CH3OH/Et3N = 50 : 1 : 1). Colorless
solid, mp 52 °C, yield 44.3 mg (37%). C20H24FN (297.4). Purity
(HPLC): 96%, tR = 18.9 min. Exact MS (APCI): m/z = calcd. for
5.2.6. (4-Azido-3-fluorobutyl)benzene (13b)26. A solution of
10b (3265 mg, 14.1 mmol) and NaN3 (1378 mg, 21.2 mmol)
in DMSO (20 mL) was heated to 65 °C for 2 h. Then, ethyl ac-
etate (60 mL) was added, and the mixture was washed with
H2O (2 × 40 mL) and brine (40 mL). The organic layer was
dried (Na2SO4), filtered, concentrated in vacuo and the resi-
due was purified by fc (6 cm, l = 8 cm, hexane/ethyl acetate =
20 : 1, 60 mL, Rf = 0.25). Colorless oil, yield 2720 mg (99%).
C10H12FN3 (193.2). Purity (HPLC): 99%, tR = 22.6 min. Exact
MS (APCI): m/z = calcd. for C10H13FN [MH − N2] 166.1032,
found 166.1035. 1H NMR (CDCl3): δ (ppm) = 1.77–2.15 (m,
1H, CH2CH2Ph), 2.68–2.88 (m, 1H, CH2CH2Ph), 3.31–3.47 (m,
2H, CH2N3), 4.54–4.72 (m, 1H, CHF), 7.19–7.24 (m, 3H,
2-CHar, 4-CHar, 6-CHar), 7.29–7.33 (m, 2H, 3-CHar, 5-CHar). 13C
NMR (CDCl3): δ (ppm) = 31.1 (d, 1C, J = 4.5 Hz, CH2Ph), 34.0
(d, 1C, J = 20.5 Hz, CH2CH2Ph), 54.5 (d, 1C, J = 21.8 Hz,
CH2N3), 91.9 (d, 1C, J = 173.5 Hz, CHF), 126.4 (1C, C-4ar),
128.6 (2C, C-2ar, C-6ar), 128.7 (2C, C-3ar, C-5ar), 140.7 (1C, C-
1
C20H25FN [MH+] 298.1966, found 298.1948. H NMR (CDCl3):
δ (ppm) = 1.34 (q, J = 11 Hz, 2H, 6-CH2, 8-CH2), 2.07 (m, 2H,
6-CH2, 8-CH2), 2.66–2.86 (m, 5H, 5-CH2, 9-CH2, 7-CH), 2.85–
2.91 (m, 2H, NCH2), 2.91–3.06 (m, 2H, CH2Ph), 4.81–4.94 (m,
1H, CHF), 7.10 (m, 4H, 1-CH, 2-CH, 3-CH, 4-CH), 7.22–7.27
(m, 3H, 1-CHaryl, 3-CHaryl, 5-CHaryl), 7.30–7.34 (m, 2H,
2-CHaryl, 4-CHaryl). 13C NMR (CDCl3): δ (ppm) = 32.2 (2C, C-5,
C-9), 34.1, 34.2 (2C, C-6, C-8), 39.6 (d, 1C, J = 21.2 Hz, CH2Ar),
50.1 (d, 1C, J = 21.0 Hz, NHCH2), 61.2 (1C, C-7), 94.1 (d, 1C, J
= 171.4 Hz, CHF), 126.37, 126.38 (2C, C-2, C-3), 126.8 (1C, C-
4
aryl), 128.7 (2C, C-3aryl, C-5aryl), 129.02, 129.03 (2C, C-1, C-4),
129.5 (2C, C-2aryl, C-6aryl), 136.83 (d, J = 5.5 Hz, 1C, C-1aryl),
142.45, 142.48 (2C, C-1a, C-4a). 19F NMR (CDCl3): δ (ppm) =
This journal is © The Royal Society of Chemistry 2017
Med. Chem. Commun.