70 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 1
Zeng et al.
(2S,3S)-2-[r-(2-(2-Fluoroethyl)phenoxy)phenylmethyl]mor-
pholine (FENET, 2). Trifluoroacetic acid (0.18 mL, 2.33 mmol)
was added dropwise to a solution of 11 (48 mg, 0.116 mmol)
obtained as above in CH2Cl2 (3 mL) at 0 °C. The reaction mixture
was allowed to reach room temperature and stirred for another 2 h.
Then 4 mL of 1 M NaOH solution was slowly added at 0 °C, and
the mixture was extracted with CH2Cl2. The extracts were com-
bined, dried over Na2SO4, and the solvent was evaporated under
reduced pressure. The crude product was purified by flash chro-
matography on silica eluted with MeOH/CH2Cl2 (10:90) to afford
2 as colorless oil (25 mg, 40% in two-step). 1H (CDCl3, 400 MHz),
δ 7.26-7.34 (m, 5 H), 7.14 (dd, J ) 1.6, 7.3 Hz, 1H), 7.01 (td, J
) 1.6, 7.9 Hz, 1H), 6.81 (td, J ) 0.9, 7.3 Hz, 1H), 6.68 (d, J ) 7.9
Hz, 1H), 5.07 (d, J ) 6.3 Hz, 1H), 4.70-4.77 (m, 1H), 4.61 (m,
1H), 3.85-3.95 (m, 2H), 3.65 (td, J ) 3.8, 10.1 Hz, 1H), 3.16 (t,
J ) 7.0 Hz, 1H), 3.11 (t, J ) 7.0 Hz, 1H), 2.78-2.82 (m, 2H),
2.52-2.57 (m, 2H), 1.79 (s, br, 1H). 13C NMR (CDCl3, 100 MHz),
(2S,3S)-N-tert-Butoxycarbonyl-2-[r-(2-methylphenylthio)phe-
nylmethyl]morpholine (14). A reaction mixture of 13 (28 mg,
0.08mmol), 2-methylbenzenethiol (19 µL, 0.16 mmol), and Cs2CO3
(52 mg, 0.16 mmol) in DMF (2 mL) was stirred at room temperature
for 18 h. The crude product was directly purified by flash
chromatography on silica eluted with hexane/EtOAc (80:20) to
afford 14 as pale-yellow oil (26 mg, 84%). 1H (CDCl3, 400 MHz),
δ 7.03-7.18 (m, 9H), 4.13 (d, J ) 7.3 Hz, 1H), 3.98-4.00 (m,
1H), 3.76 (m, br, 3H), 3.53-3.59 (m, 1H), 2.94-3.00 (m, 1H),
2.77 (m, br, 1H), 2.27 (s, 3H), 1.38 (s, 9H).
(2S,3S)-2-[r-(2-Methylphenylthio)phenylmethyl]morpho-
line (MESNET, 4). Trifluoroacetic acid (0.1 mL, 1.31 mmol) was
added dropwise to a solution of 14 (35 mg, 0.09 mmol) in CH2Cl2
(1.5 mL) at 0 °C. The reaction mixture was allowed to reach room
temperature and stirred for another 2 h. Then 2 mL of 1 M NaOH
solution was slowly added at 0 °C and the mixture was extracted
with CH2Cl2. The extracts were combined, dried over Na2SO4, and
the solvent was evaporated under reduced pressure. The crude
product was purified by flash chromatography on silica eluted with
MeOH/CH2Cl2 (10:90) to afford 4 as pale-yellow oil (19 mg, 72%),
which was solidified in a freezer. 1H (CDCl3, 400 MHz), δ
7.15-7.21 (m, 6H), 7.00-7.06 (m, 2H), 6.93-6.97 (m, 1H), 4.13
(d, J ) 7.9 Hz, 1H), 4.00-4.03 (m, 1H), 3.82-3.87 (m, 1H), 3.66
(td, J ) 2.8, 11.1 Hz, 1H), 2.87 (td, J ) 3.2, 11.1 Hz, 1H)
2.70-2.80 (m, 1H), 2.59-2.69 (m, 2H), 2.26 (s, 3H), 2.06 (s, br,
1H). 13C NMR (CDCl3, 100 MHz), δ 140.7, 139.2, 133.7, 133.5,
130.2, 128.6, 128.4, 127.6, 127.3, 126.2, 79.4, 68.6, 56.6, 49.8,
45.8, 20.9. HRMS [MH]+ calcd for C18H22ONS: 300.1416; found:
300.1414. Anal. (C18H21ONS) C, H, N.
δ 156.4, 137.8, 131.1, 128.8, 128.5, 128.0, 127.2, 125.9 (d, JC-F
)
7.6 Hz), 121.0, 113.6, 83.4 (d, JC-F ) 167.1 Hz), 81.8, 79.5, 68.3,
47.7, 46.0, 32.2 (d, JC-F ) 21.4 Hz). HRMS [MH]+ calcd for
C19H23FNO2: 316.1707; found: 316.1707. Anal. (C19H22FNO2) C,
H, N.
(2S,3S)-N-tert-Butoxycarbonyl-2-[r-(2-(3-fluoropropyl)phe-
noxy)phenylmethyl]morpholine (12). To a mixture of 6 (60 mg,
0.2 mmol), 2-(3-fluoropropyl)phenol (10) (58 mg, 0.4 mmol), and
triphenylphosphine (108 mg, 0.4 mmol) in dry THF (4 mL) was
added diisopropyl azodicarboxylate (79 µL, 0.4 mmol) at 0 °C.
The reaction mixture was allowed to reach room temperature and
stirred for 24 h. The crude product was concentrated under reduced
pressure and was loaded on a short silica column eluted with
hexane/EtOAc (85:15), and 100 mL fractions were collected. After
evaporating the solvent, colorless oil (72 mg) was obtained, and
NMR shows it is the mixture of 12 and 10 (3.5:1), which was used
without any further purification.
(2S,3S)-2-[r-(2-(3-Fluoropropyl)phenoxy)phenylmeth-
yl]morpholine (FPNET, 3). Trifluoroacetic acid (0.19 mL, 2.48
mmol) was added dropwise to a solution of 12 (56 mg, 0.13 mmol)
obtained as above in CH2Cl2 (3 mL) at 0 °C. The reaction mixture
was allowed to reach room temperature and stirred for another 2 h.
Then 4 mL of 1 M NaOH solution was slowly added at 0 °C and
the mixture was extracted with CH2Cl2. The extracts were com-
bined, dried over Na2SO4, and the solvent was evaporated under
reduced pressure. The crude product was purified by flash chro-
matography on silica eluted with MeOH/CH2Cl2 (10:90) to afford
3 as colorless oil (29 mg, 44% in two-step). 1H (CDCl3, 400 MHz),
δ 7.30-7.35 (m, 4H), 7.26-7.28 (m, 1H), 7.10 (dd, J ) 1.6, 7.3
Hz, 1H), 6.97 (td, J ) 1.4, 8.1 Hz, 1H), 6.79 (td, J ) 0.9, 8.1 Hz,
1H), 6.65 (d, J ) 8.1 Hz, 1H), 5.07 (d, J ) 6.2 Hz, 1H), 4.52 (td,
J ) 2.3, 5.7 Hz, 1H), 4.44 (td, J ) 2.4, 5.7 Hz, 1H), 3.91-3.93
(m, 1H), 3.86-3.90 (m, 1H), 3.64 (td, J ) 2.9, 11.3 Hz, 1H),
2.75-2.83 (m, 4H), 2.54-2.63 (m, 2H), 2.01-2.10 (m, 2H), 1.82
(s, br, 1H). 13C NMR (CDCl3, 100 MHz), δ 156.2, 137.9, 130.4,
(2S,3S)-N-tert-Butoxycarbonyl-2-[r-(2-iodophenoxy)phenyl-
methyl]morpholine (17). To a mixture of 6 (30 mg, 0.1 mmol),
2-iodophenol (44 mg, 0.2 mmol), and triphenylphosphine (53 mg,
0.2 mmol) in dry THF (2 mL) was added diisopropyl azodicar-
boxylate (40 µL, 0.2 mmol) at 0 °C. The reaction mixture was
allowed to reach room temperature and stirred during 48 h. The
crude product was concentrated under reduced pressure and purified
by flash chromatography on silica eluted with hexane/EtOAc (80:
1
20) to afford 17 as colorless oil (32 mg, 64%). H (CDCl3, 400
MHz), δ 7.72-7.74 (m, 1H), 7.25-7.38 (m, 5H), 7.06-7.11 (m,
1H), 6.60-6.62 (m, 2H), 5.30 (m, 1H), 3.86-3.94 (m, 4H),
3.54-3.60 (m, 1H), 2.80-2.90 (m, 1H), 2.70-2.75 (m, 1H), 1.42
(s, 9H). 13C NMR (CDCl3, 100 MHz), δ 156.1, 155.0, 139.7, 136.2,
129.4, 128.7, 128.6, 127.5, 123.0, 113.9, 82.1, 80.9, 80.2, 67.0,
44.8, 42.3, 28.6. HRMS [MH]+ calcd for C22H27O4NI: 496.0979;
found: 496.0978.
(2S,3S)-N-tert-Butoxycarbonyl-2-[r-(2-trimethylstannylphe-
noxy)phenylmethyl]morpholine (15). To a solution of 17 (27 mg,
0.055 mmol) in 1, 2-dimethoxyethane (2 mL) was added Pd(PPh3)4
(7 mg) and hexamethylditin (56 µL, 0.27 mmol). The mixture was
purged under Ar for 15 min and then heated at 80 °C for 18 h. The
solvent was evaporated and the crude product was purified by flash
chromatography on silica eluted with hexane/EtOAc/Et3N (92:8:
1
130.3, 128.7, 128.3, 127.3, 127.2, 120.9, 113.5, 84.0 (d, JC-F
)
0.1) to afford 15 as colorless oil (23 mg, 80%). H (CDCl3, 400
165.9 Hz), 81.5, 79.5, 68.3, 47.6, 46.0, 30.9 (d, JC-F ) 18.7 Hz),
MHz), δ 7.25-7.35 (m, 6H), 7.06-7.10 (m, 1H), 6.85-6.88 (m,
1H), 6.53 (d, J ) 8.2 Hz, 1H), 5.14 (m, 1H), 3.90-3.92 (m, 1H),
3.71-3.80 (m, 2H), 3.61-3.65 (m, 1H), 3.50-3.56 (m, 1H), 2.87
(m, 1H), 2.61-2.67 (m, 1H), 1.55 (s, 9H), 1.40 (s, 9H).
(2S,3S)-N-tert-Butoxycarbonyl-2-[r-(2-iodophenylthio)phenyl-
methyl]morpholine (18). A reaction mixture of 13 (71 mg, 0.2
mmol), 2-iodobenzenethiol (94 mg, 0.4 mmol), and Cs2CO3 (130
mg, 0.4 mmol) in DMF (2 mL) was stirred at room temperature
for 18 h. The crude product was directly purified by flash
chromatography on silica eluted with hexane/EtOAc (80:20) to
afford 18 as colorless oil (65 mg, 63%). 1H (CDCl3, 400 MHz), δ
7.45-7.47 (m, 1H), 7.13-7.27 (m, 6H), 6.92-7.02 (m, 2H), 4.41
(d, J ) 7.3 Hz, 1H), 3.98 (d, J ) 11.8 Hz, 1H), 3.76-3.80 (m,
3H), 3.52-3.58 (m, 1H), 2.97-3.04 (m, 1H), 2.83 (m, br, 1H),
1.38 (s, 9H).
1
26.6 (d, JC-F ) 18.7 Hz). HRMS [MH]+ calcd for C20H25FNO2:
330.1864; found: 330.1859. Anal. (C20H24FNO2) C, H, N.
(2S,3R)-N-tert-Butoxycarbonyl-2-[r-bromo(phenyl)methyl-
]morpholine (13). To a solution of 5 (118 mg, 0.4 mmol) in CH2Cl2
(3 mL) was added PPh3 (210 mg, 0.8 mmol) at room temperature.
The mixture was then cooled down to 0 °C, and a solution of CBr4
(266 mg, 0.8 mmol) in CH2Cl2 (1 mL) was then added dropwise at
this temperature. The reaction mixture was warmed up to room
temperature and stirring was continued for 30 min. The solvent
was evaporated and the crude product was purified by flash
chromatography on silica eluted with hexane/EtOAc (80:20) to
1
afford 13 as colorless oil (107 mg, 75%). H (CDCl3, 400 MHz),
δ 7.26-7.41 (m, 5H), 4.84 (d, J ) 7.6 Hz, 1H), 4.36 (s, br, 1H),
3.79-3.86 (m, 3H), 3.46 (td, J ) 2.8, 11.4 Hz, 1H), 2.92-2.96
(m, 2H), 1.46 (s, 9H). 13C NMR (CDCl3, 100 MHz), δ 154.8, 138.7,
128.8, 128.6, 80.5, 77.9, 66.9, 53.3, 47.0 (br), 43.2 (br), 28.6. HRMS
[MH]+ calcd for C16H23O3N79Br: 356.0856; found: 356.0854.
(2S,3S)-N-tert-Butoxycarbonyl-2-[r-(2-trimethylstannylphe-
nylthio)phenylmethyl]morpholine (16). To a stirred solution of
n-butyllithium (0.97 mL, 1.6 M in hexanes, 1.55 mmol) and