The Journal of Organic Chemistry
Article
7.37−7.25 (m, 5H), 5.47 (s, 0.7H), 5.18 (s, 0.3H), 4.89 (s, 0.7H), 4.33
(s, 0.7H), 4.02 (s, 0.3H), 3.58 (s, 0.3H), 3.31 (s, 1H), 2.84 (s, 0.7H),
2.36−2.14 (m, 0.3H), 1.98−1.88 (m, 1H), 1.79 (s, 1H), 1.54 (s, 9H),
1.26−1.16 (m, 1H), 0.95−0.8 (m, 1H). The analytical data are
consistent with the previously reported characterization.41
(S)-tert-Butyl 2-((S)-Hydroxy(phenyl)methyl)pyrrolidine-1-
carboxylate (15b). According to general procedure TP3 (Method
1), 12 (1 equiv, 1 g, 3.6 mmol) was dissolved in MeOH (30 mL) and
treated with NaBH4 (4 equiv, 0.55 g, 14.5 mmol) to afford 15b as
colorless oil (0.73 g, 72%). After purification by reverse phase C18
column chromatography (MeOH/H2O). 1H NMR (400 MHz,
CDCl3): δ 7.35−7.24 (m, 5H), 5.81 (s, 0.7H), 5.41 (s, 0.3H), 5.16−
4.60 (m, 1H), 4.56−4.21 (m, 1H), 4.12−4.00 (m, 0.8H), 3.53−3.16
(m, 2H), 2.79 (s, 0.2H), 1.75−1.58 (m, 3H), 1.48 (s, 9H). The
analytical data are consistent with the previously reported character-
ization.41
(S)-tert-Butyl 2-((R)-((1,3-Dioxoisoindolin-2-yl)oxy)(phenyl)-
methyl)pyrrolidine-1-carboxylate (18a). According to general
procedure TP4, 15a (1 equiv, 500 mg, 1.8 mmol) was treated with
NHPI (1.5 equiv, 441 mg, 2.7 mmol), PPh3 (1.8 equiv, 851 mg, 3.2
mmol), and DEAD (1.8 equiv, 0.51 mL, 3.2 mmol) in THF (15 mL) at
0 °C. The crude was purified by silica gel column chromatography
(heptane/EtOAc = 4:1) to afford 18a as a white solid (716 mg, 94%).
1H NMR (400 MHz, CDCl3): δ 7.72−7.38 (m, 6H), 7.30−7.19 (m,
3H), 5.88 (s, 0.4H), 5.68 (s, 0.6H), 4.03 (m, 1H), 3.59−3.32 (m, 2H),
2.50−2.19 (m, 1H), 2.05 (m, 1H), 1.75 (m, 2H), 1.40 (s, 4H), 1.36 (s,
5H). 13C{1H} NMR (101 MHz, CDCl3): δ 163.6, 154.8, 134.4, 129.2,
128.6, 128.2, 127.8, 127.5, 123.5, 88.9, 77.4, 61.8, 46.8, 29.9, 22.8, 14.3.
HRMS (ESI) m/z: calcd for C24H26N2O5 [M + Na]+, 445.1740; found,
445.1746.
(5S,6S)-5-Methyl-6-phenyl-5,6-dihydro-4H-1,2,4-oxadiazin-
3-amine (19a). Step 1: tert-butyl((1S,2S)-1-(aminooxy)-1-phenyl-
propan-2-yl)carbamate (39a). According to general procedure TP5,
16a (1 equiv, 400 mg, 1 mmol) in EtOH (15 mL) was treated with
hydrazine hydrate (15 equiv, 0.73 mL, 15.1 mmol). The crude was
purified by silica gel column chromatography (heptane/EtOAc = 2:1)
to afford tert-butyl((1S,2S)-1-(aminooxy)-1-phenylpropan-2-yl)-
tert-Butyl((1S,2S)-1-((1,3-dioxoisoindolin-2-yl)oxy)-1-phe-
nylpropan-2-yl)carbamate (16a). According to general procedure
TP4, 13a (1 equiv, 500 mg, 2 mmol) was reacted with NHPI (1.5 equiv,
487 mg, 3 mmol), PPh3 (1.8 equiv, 939 mg, 3.6 mmol), and DEAD (1.8
equiv, 0.56 mL, 3.6 mmol) in THF (15 mL) at 0 °C. The crude was
purified by silica gel column chromatography (heptane/EtOAc = 5:1)
1
carbamate 39a as colorless oil (245 mg, 91%). H NMR (400 MHz,
1
to afford 16a as a white solid (702 mg, 89%). H NMR (400 MHz,
CDCl3): δ 7.40−7.33 (m, 2H), 7.33−7.26 (m, 3H), 5.32 (s, 2H), 4.64−
4.53 (m, 1H), 4.49 (d, J = 5.6 Hz, 1H), 3.99 (s, 1H), 1.40 (s, 9H), 1.05
(d, J = 6.8 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 155.5, 138.6,
128.6, 128.1, 127.5, 89.1, 79.4, 49.9, 28.5, 17.6.
CDCl3): δ 7.76−7.71 (m, 2H), 7.70−7.65 (m, 2H), 7.49−7.43 (m,
2H), 7.37−7.30 (m, 3H), 5.22 (d, J = 6.5 Hz, 1H), 5.13 (s, 1H), 4.18 (q,
J = 7.0 Hz, 1H), 1.42 (s, 9H), 1.20 (d, J = 6.8 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3): δ 163.7, 155.4, 135.6, 134.5, 129.2, 129.0, 128.4,
128.4, 123.6, 90.9, 79.5, 50.1, 28.5, 17.9. HRMS (ESI) m/z: calcd for
C22H24N2O5 [M + Na]+, 419.1590; found, 419.1583.
Step 2: (1S,2S)-1-(aminooxy)-1-phenylpropan-2-amine dihydro-
chloride (40a). According to general procedure TP6, tert-butyl-
((1S,2S)-1-(aminooxy)-1-phenylpropan-2-yl)carbamate 39a (1 equiv,
100 mg, 0.38 mmol) was treated with a hydrogen chloride solution in
dioxane (4 M, 5 mL) to afford (1S,2S)-1-(aminooxy)-1-phenylpropan-
tert-Butyl((1R,2S)-1-((1,3-dioxoisoindolin-2-yl)oxy)-1-phe-
nylpropan-2-yl)carbamate (16b). According to general procedure
TP4, 13b (1 equiv, 500 mg, 2 mmol) was reacted with NHPI (2 equiv,
649 mg, 4 mmol), PPh3 (2.5 equiv, 1.3 g, 5 mmol), and DEAD (2.5
equiv, 0.78 mL, 5 mmol) in THF (20 mL) at rt. The crude was purified
by silica gel column chromatography (heptane/EtOAc = 5:1) to afford
1
2-amine dihydrochloride 40a as a white solid (89.8 mg, 100%). H
NMR (400 MHz, DMSO-d6): δ 10.79 (s, br, 3H), 8.56 (s, br, 3H),
7.57−7.34 (m, 5H), 5.17 (d, J = 9.1 Hz, 1H), 3.58 (dt, J = 13.6, 6.8 Hz,
1H), 0.93 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
134.1, 129.7, 128.9, 128.3, 86.4, 49.3, 15.1.
1
16b as colorless oil (757 mg, 96%). H NMR (400 MHz, CDCl3): δ
7.77−7.72 (m, 2H), 7.71−7.67 (m, 2H), 7.56 (d, J = 7.5 Hz, 2H),
7.39−7.27 (m, 3H), 5.43 (s, 1H), 5.40 (s, 1H), 4.06 (s, 1H), 1.43 (s,
9H), 1.24 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
163.8, 155.4, 136.3, 134.6, 129.0, 128.6, 128.2, 127.6, 123.6, 91.5, 79.5,
51.1, 28.5, 14.2. HRMS (ESI) m/z: calcd for C22H24N2O5 [M + Na]+,
419.1583; found, 419.1590.
tert-Butyl((1S,2S)-1-((1,3-dioxoisoindolin-2-yl)oxy)-3-meth-
yl-1-phenylbutan-2-yl)carbamate (17a). According to general
procedure TP4, 14a (1 equiv, 500 mg, 1.8 mmol) was treated with
NHPI (1.5 equiv, 438 mg, 2.7 mmol), PPh3 (1.8 equiv, 845 mg, 3.2
mmol), and DEAD (1.8 equiv, 0.51 mL, 3.2 mmol) in THF (15 mL) at
0 °C. The crude was purified by silica gel column chromatography
(heptane/EtOAc = 4:1), to afford 17a as a white solid (615 mg, 81%).
1H NMR (400 MHz, CDCl3): δ 7.72−7.64 (m, 4H), 7.51−7.47 (m,
Step 3: (5S,6S)-5-methyl-6-phenyl-5,6-dihydro-4H-1,2,4-oxadiazin-
3-amine (19a). According to general procedure TP7, the above
(1S,2S)-1-(aminooxy)-1-phenylpropan-2-amine dihydrochloride 40a
(1 equiv, 50 mg, 0.21 mmol) was dissolved in MeCN (10 mL) and
treated successively with TEA (4 equiv 116.2 μL, 0.84 mmol) and a
solution of BrCN (1.1 equiv, 24.4 mg, 0.23 mmol) in MeCN (0.5 mL)
to afford the title compound 19a (28.4 mg, 71%) as a white solid after
purification by reverse phase C18 column chromatography (MeCN/
H2O). Compound 19a was recrystallized in MeCN at 4 °C. 1H NMR
(400 MHz, DMSO-d6): δ 7.39−7.27 (m, 5H), 6.10 (s, 1H), 4.39 (s,
2H), 3.82 (d, J = 8.5 Hz, 1H), 3.40−3.34 (m, 1H), 0.84 (d, J = 6.3 Hz,
3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 153.9, 138.4, 128.2,
128.1, 127.7, 80.9, 50.7, 17.6. HRMS (ESI) m/z: calcd for C10H14N3O
[M + H]+, 192.1137; found, 192.1139.
2H), 7.33−7.27 (m, 3H), 5.52 (d, J = 4.8 Hz, 1H), 5.12 (d, J = 10.2 Hz,
1H), 3.81 (ddd, J = 10.1, 6.8, 4.7 Hz, 1H), 1.98−1.86 (m, 1H), 1.39 (s,
9H), 1.15 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3): δ 163.7, 156.1, 136.5, 134.5, 129.0, 128.9, 128.3,
128.1, 123.5, 88.2, 79.2, 60.0, 30.6, 28.5, 20.3, 18.5. HRMS (ESI) m/z:
calcd for C24H28N2O5 [M + Na]+, 447.1896; found, 447.1902.
tert-Butyl((1S,2S)-1-((1,3-dioxoisoindolin-2-yl)oxy)-3-meth-
yl-1-phenylbutan-2-yl)carbamate (17b). According to general
procedure TP4, 14b (1 equiv, 400 mg, 1.4 mmol) was treated NHPI (3
equiv, 700 mg, 4.3 mmol), PPh3 (3.5 equiv, 1.3 g, 5 mmol), and DEAD
(1.8 equiv, 0.79 mL, 5 mmol) in THF (15 mL) at 45 °C in an oil bath.
The crude was purified by silica gel column chromatography (heptane/
EtOAc = 5:1) to afford 17b as a white solid (450 mg, 74%). 1H NMR
(400 MHz, CDCl3): δ 7.72−7.67 (m, 2H), 7.67−7.64 (m, 2H), 7.53−
7.46 (m, 2H), 7.33−7.26 (m, 3H), 5.36 (d, J = 7.6 Hz, 1H), 4.50 (d, J =
10.7 Hz, 1H), 4.24−4.15 (m, 1H), 2.32−2.19 (m, 1H), 1.28 (s, 7H),
1.26 (s, 2H), 1.08 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 163.6, 155.6, 135.8, 134.4, 129.1, 128.9,
128.8, 128.1, 123.5, 89.3, 79.3, 57.7, 28.3, 28.1, 20.6, 16.4. HRMS (ESI)
m/z: calcd for C24H28N2O5 [M + Na]+, 447.1896; found, 447.1902.
(5S,6R)-5-Methyl-6-phenyl-5,6-dihydro-4H-1,2,4-oxadiazin-
3-amine (19b). Step 1: tert-butyl((1R,2S)-1-(aminooxy)-1-phenyl-
propan-2-yl)carbamate (39b). According to general procedure TP5,
16b (1 equiv, 400 mg, 1 mmol) in EtOH (15 mL) was treated with
hydrazine hydrate (15 equiv, 0.73 mL, 15.1 mmol). The crude was
purified by silica gel column chromatography (heptane/EtOAc = 2:1)
to afford tert-butyl((1R,2S)-1-(aminooxy)-1-phenylpropan-2-yl)-
1
carbamate 39b as colorless oil (258 mg, 96%). H NMR (400 MHz,
CDCl3): δ 7.39−7.32 (m, 2H), 7.31−7.26 (m, 3H), 5.50 (s, br, 2H),
4.78−4.65 (m, 1H), 4.61 (d, J = 3.4 Hz, 1H), 4.15−4.00 (m, 1H), 1.45
(s, 9H), 0.98 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
155.6, 138.2, 128.5, 127.9, 127.1, 89.1, 79.3, 49.2, 28.6, 15.5.
Step 2: (1R,2S)-1-(aminooxy)-1-phenylpropan-2-amine dihydro-
chloride (40b). According to general procedure TP6, tert-butyl-
((1R,2S)-1-(aminooxy)-1-phenylpropan-2-yl)carbamate 39b (1 equiv,
100 mg, 0.38 mmol) was treated with a hydrogen chloride solution in
dioxane (4 M, 5 mL) to afford (1R,2S)-1-(aminooxy)-1-phenylpropan-
2-amine dihydrochloride 40b as a white solid (88.9 mg, 99%). 1H NMR
(400 MHz, DMSO-d6): δ 10.99 (s, br, 3H), 8.46 (s, br, 3H), 7.51−7.38
(m, 5H), 5.47 (d, J = 3.8 Hz, 1H), 3.59 (dt, J = 7.0, 3.1 Hz, 1H), 1.08 (d,
H
J. Org. Chem. XXXX, XXX, XXX−XXX