Jul-Aug 2002
Synthesis of N -Substituted[1,3,4]oxadiazinan-2-ones Derived from Norephedrine
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(1R,2S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-methoxy-
acetamide (3d).
(1R,2S)-2-Amino-N-propyl-1-phenyl-1-propanol (4a).
The resulting white solid was recrystallized with EtOAc-
Recrystalization with EtOAc and hexanes yielded (3d) as a
hexanes (1:1) to produce 4a in 99% yield: R = 0.28 (1:1,
f
1
white crystalline solid in 89% yield. Mp: 84-86 °C; R = 0.12
EtOAc:hexanes). H NMR (CDCl ): δ 0.83 (d, 3H, J = 6.6 Hz),
f
3
1
(EtOAc/hexanes, 1:1). H NMR (CDCl ): δ 1.06 (d, 3H, J = 7.2
0.94 (t, 3H, J = 7.5 Hz), 1.49-1.59 (m, 2H), 2.62-2.75 (m, 2H),
3
Hz), 3.21 (bs, 1H), 3.40 (s, 3H), 3.92 (s, 2H), 4.31-4.39 (m, 1H),
2.91-2.96 (m, 1H), 4.79 (d, 1H, J = 3.7 Hz), 7.22-7.35 (m, 5H).
4.89 (d, 1H, J = 2.9 Hz), 6.62 (bs, 1H), 7.27-7.34 (m, 1H),
13
C NMR (CDCl ): δ 11.7, 14.4, 23.2, 49.0, 58.4, 73.1, 126.0,
3
13
7.35-7.36 (m, 4H). C NMR (CDCl ): δ 14.2, 50.3, 59.1, 71.7,
-1
3
126.9, 128.0, 141.6. IR (neat): 3474, 3245, 2969, 1174 cm .
76.0, 126.2, 127.4, 127.4, 140.8, 169.9. IR (KBr): 3400-3100,
EI-MS, m/z (%): 190 (1), 105 (57), 86 (100), 77 (49). HRMS
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3297, 1652, 1547, 1117, 759, 704 cm . EI-MS, m/z (%): 175(25),
Calc'd for C H NO: 194.1545. Found: 194.1540.
12 19
132 (6), 117 (100), 99 (75).
(1R,2S)-2-Amino-N-(2-phenylethyl)-1-phenyl-1-propanol (4b).
Anal. Calc'd for C
H NO : C, 64.55; H, 7.67; N, 6.27.
12 17 3
Found: C, 64.51; H, 7.67; N, 6.39.
The resulting white solid was recrystallized with EtOAc-
(1R,2S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-phenoxy-
acetamide (3e).
hexanes (1:1) to produce the title compound in 87% yield. Mp:
1
75-77 °C; R = 0.33 (EtOAc/hexanes, 1:1). H NMR (CDCl ): δ
f
3
0.79 (d, 3H, J = 6.6 Hz), 2.73-2.86 (m, 2H), 2.89-3.03 (m, 3H),
4.72 (d, 1H, J = 4.0 Hz), 7.18-7.25 (m, 4H), 7.27-7.33 (m, 6H).
The product was recrystallized from methylene chloride and
hexanes to afford the title compound in 94% yield. Mp: 125-127
13
C NMR (CDCl ): δ 14.8, 36.9, 48.6, 58.5, 73.3, 126.3, 126.5,
1
3
°C; R = 0.42 (EtOAc:hexanes, 1:1). H NMR (CDCl ): δ 1.05
f
3
127.3, 128.3, 128.7, 128.9, 140.0, 141.5. IR (KBr): 3061, 747,
(d, 3H, J = 6.6 Hz), 2.52 (bs, 1H), 4.39-4.44 (m, 1H), 4.51
(s, 2H), 4.89 (d, 1H, J = 2.9 Hz), 6.76 (d, 1H, J = 8.1 Hz),
-1
703 cm . EI-MS, m/z (%): 105 (44), 77 (36), 56 (100).
Anal. Calc'd for C H NO: C, 79.96; H, 8.29; N, 5.49. Found:
C, 79.66; H, 8.36; N, 5.57.
6.90-6.92 (m, 2H), 7.04 (t, 1H, J = 7.3 Hz), 7.26-7.36 (m, 7H).
17 21
13
C NMR (CDCl ): δ 14.1, 50.2, 67.0, 75.5, 114.6, 122.0, 126.1,
3
127.5, 128.1, 129.6, 140.5, 156.9, 168.3. IR (KBr): 3350-3100
(bs), 3326, 3066, 2993, 1654, 1244, 758, 704 cm . HRMS Calc'd
(1R,2S)-2-Amino-N-(2,2-dimethylpropyl)-1-phenyl-1-propanol
(4c).
-1
for C H NO , 285.1365. Found, 285.1359.
17 19
3
Anal. Calc'd for C
H NO : C, 71.56; H, 6.71; N, 4.91.
The title compound was obtained in 89% yield after
17 19 3
Found: C, 71.43; H, 6.67; N, 5.12.
recrystallization from ethyl acetate and hexanes. R = 0.58
f
1
(EtOAc). H NMR (CDCl ): δ 0.79 (d, 3H, J = 6.2 Hz), 0.94
3
(1R,2S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-benzyloxyac-
etamide (3f).
(s, 9H), 2.47 (AB spin system, 2H, ∆ν = 63.7 Hz, J = 11.0 Hz),
2.88 (dq, 1H, J = 6.6, 4.0 Hz), 4.74 (d, 1H, J = 4.0 Hz), 7.23-7.36
This process afforded a white solid which was recrystallized
with EtOAc-hexanes to yield the title compound in 88% yield as
13
(m, 5H). C NMR (CDCl ): δ 14.8, 27.5, 31.2, 58.8, 59.3, 72.5,
3
125.8, 126.7, 127.8, 141.3. IR (KBr): 3416, 2954, 1494, 741, 701
a white solid. Mp: 71-72 °C; R = 0.42 (EtOAc:hexanes, 1:1).
-1
f
cm . HRMS Calc'd for C
222.1857.
H NO : 222.1858. Found:
17 22 2
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H NMR (CDCl ): δ 0.96 (d, 3H, J = 7.0 Hz), 3.29 (bs, 1H), 3.91
3
(s, 2H), 4.24-4.26 (m, 1H), 4.46 (s, 2H), 4.78 (d, 1H, J = 2.9 Hz),
6.66 (d, 1H, J = 7.7 Hz), 7.19-7.30 (m, 10H). C NMR (CDCl ):
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(1R,2S)-2-Amino-N-(2-methoxyethyl)-1-phenyl-1-propanol (4d).
3
δ 14.2, 50.1, 69.1, 73.3, 75.7, 126.1, 127.3, 127.7, 128.0, 128.4,
The title compound was recovered as a viscous oil. Yield:
136.6, 140.8, 169.7. IR (KBr): 3300, 2938, 1649, 1098, 757, 700
1
94%. Compound 4d: H NMR (CDCl ): δ 0.83 (d, 3H, J = 6.6
3
-1
cm .
Hz), 2.43 (bs, 1H), 2.84-2.90 (m, 2H), 2.92-2.98 (m, 2H), 3.37
Anal. Calc'd for C
H NO : C, 72.22; H, 7.07; N, 4.68.
18 21 3
(s, 3H), 3.54 (d, 2H, J = 4.0 Hz), 4.80 (d, 1H, J = 3.6 Hz),
Found C, 72.19; H, 7.11; N, 4.85.
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7.33-7.34 (m, 5H). C NMR (CDCl ): δ 14.2, 46.6, 58.6, 71.9,
3
General Procedure for the Preparation of the Amine Derivative 4.
72.8, 74.4, 126.0, 127.0, 128.0, 141.3. IR (neat): 306, 1449, 1094,
-1
+
752, 703 cm . HRMS Calc'd for C
H NO (M + H):
12 20 2
Into a 3-necked 5 L nitrogen purged round bottom flask
210.1494. Found: 210.1498.
equipped with a reflux condenser was placed NaBH (11.4 g,
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301 mmol) and THF (250 mL). To this stirred mixture was added
the norephedrine amide (3) (126 mmol). A 250 mL addition
funnel equipped with a pressure equalizing arm was filled with
iodine (36.7 g, 144 mmol) and THF (250 mL) which was then
attached to the 3-necked round bottom flask. The iodine mixture
was added over a period of 30 minutes followed by heating of the
resulting mixture to reflux. The mixture was maintained at reflux
for 15 hours and was then cooled to room temperature followed
by cautious addition of methanol (100 mL) to destroy any remain-
(1R,2S)-2-Amino-N-(2-phenoxyethyl)-1-phenyl-1-propanol (4e).
The title compound was recrystallized from hexanes and
methylene chloride to afford a white solid in 81% yield. Mp =
1
90-91 °C; R = 0.10 (EtOAc/hexanes, 1:1). H NMR (CDCl ): δ
f
3
0.86 (d, 3H, J = 6.6 Hz), 2.96-3.05 (m, 2H), 3.11-3.16 (m, 1H),
4.06-4.08 (m, 2H), 4.77 (d, 1H, J = 4.0 Hz), 6.89 (d, 2H, J = 8.4
13
Hz), 6.96 (t, 1H, J = 7.3 Hz), 7.23-7.33 (m, 7H). C NMR
(CDCl ): δ 14.1, 46.0, 58.3, 67.0, 73.4, 114.3, 120.7, 126.0,
3
126.9, 127.9, 129.3, 141.5, 158.5. IR (KBr): 3340, 3060, 2976,
ing NaBH . The solvent was then removed after all signs of
4
-1
1598, 1244, 757, 701 cm . HRMS Calc'd for C
272.1651. Found, 272.1650.
H NO ,
NaBH activity were gone. The resulting white solid was stirred in
17 22 2
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aqueous KOH (100 mL, 2 M) for 1 hour. The resulting mixture
was then extracted with EtOAc (3 x 75 mL), washed with aqueous
brine, dried (Na SO ) and the solvent was removed.
Anal. Calc'd for C
H NO : C, 75.25; H, 7.80; N, 5.16.
17 21 2
Found: C, 75.00; H, 7.88; N, 5.32.
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