July 2010
Synthesis and X-ray Crystal Structures of Chiral, Nonracemic
5,6-Dihydro-4H-1,3,4-oxadiazines
987
title compound was isolated by recrystallization (EtOAc:hex-
anes). White solid (31%), Mp ¼ 119–120ꢀC. [a]D24 ¼ ꢁ58.6 (c
1656, 1066, 756, and 700 cmꢁ1
.
ESI-HRMS calcd. for
C13H19N2O (M þ Hþ): 219.1497. Found: 219.1489.
1
(5S,6S)-4-Isopropyl-5-methyl-2,6-diphenyl-5,6-dihydro-4H-
1,3,4-oxadiazine (18). Hydrazide 14 (0.50 g, 1.60 mmol) was
combined with H2SO4 (5 mL, 12M) and stirred for 2 h. The
solution was diluted with H2O (100 mL) and neutralized with
NaHCO3. The organic layer was diluted with EtOAc (100
mL), washed with brine (50 mL), dried with MgSO4, and the
solvents were removed via rotary evaporation. The title prod-
uct was isolated by flash column chromatography (hexanes:-
0.58, CHCl3). H NMR (400 MHz, CDCl3) d: 0.86 (d, J ¼ 6.6
Hz, 3H), 1.14 (d, J ¼ 6.6 Hz, 3H), 1.20 (d, J ¼ 6.6 Hz, 3H),
3.09–3.11 (m, 1H), 3.43–3.50 (m, 1H), 5.00 (d, J ¼ 2.0 Hz,
1H), 7.19–7.78 (m, 10H). 13C NMR (100 MHz, CDCl3) d: 9.9,
17.0, 18.9, 52.3, 63.3, 73.2125.7, 127.7, 127.1, 128.0, 128.7,
131.9, 133.2, 141.3, and 168.9. IR (diamond): 3264, 1653, 748,
and 680 cmꢁ1. ESI-HRMS calcd. for C19H25N2O2 (M þ Hþ):
313.1916. Found: 313.1913.
TEA, 97.5:2.5). White solid (40%), Mp ¼ 160–162ꢀC. [a]D24
¼
trans-(5S,6S)-4,5-Dimethyl-2-(1-naphthyl)-6-phenyl-5,6-
dihydro-4H-1,3,4-oxadiazine (15). Hydrazide 12 (0.50 g,
1.50 mmol) was combined with H2SO4 (5 mL, 12M) was
stirred for 2 h. The solution was diluted with H2O (100 mL)
and neutralized with NaHCO3. The organic layer was diluted
with EtOAc (100 mL), washed with brine (50 mL), and dried
(MgSO4). The title compound was isolated by trituration with
pentane. This process afforded the title compound as a ꢂ7:1
mixture of the trans- and cis-isomers of the title oxadiazine.
Yellow solid (28%), Mp ¼ 140–142ꢀC. [a]D25 ¼ þ 56.9 (c
þ175.0 (c 0.25, CHCl3). IR (diamond): 1625, 1027, 756, and
1
686 cmꢁ1. H NMR (400 MHz, CDCl3) d (ppm): 1.00 (d, J ¼
6.2 Hz, 3H), 1.04 (d, J ¼ 6.2 Hz, 3H), 1.40 (d, J ¼ 6.6 Hz,
3H), 2.92 (dq, J ¼ 12.9, 6.6 Hz, 1H), 3.52 (septet, J ¼ 6.6 Hz,
1H), 5.04 (d, J ¼ 6.6 Hz, 1H), 7.25–7.86 (m, 10H). 13C NMR
(100 MHz, CDCl3) d (ppm): 13.9, 15.6, 21.4, 50.2, 53.4, 82.4,
125.1, 127.6, 127.9, 128.5, 128.6, 133.2, 138.6, and 145.3.
ESI-HRMS calcd. for C19H23N2O (M þ Hþ): 295.1810.
Found: 295.1798.
1
General procedure for the formation of hydrazides 20a
and 20b. Hydrazine 19 (0.700 g, 3.36 mmol) was combined
with dichloromethane (17 mL) and TEA (0.515 g, 3.70 mmol)
and this mixture was cooled to 0ꢀC. The anhydride (0.798 g,
3.53 mmol) was then added. After 24 h, the reaction was
diluted by the addition of a saturated solution of ammonium
chloride (100 mL) and diluted with CH2Cl2 (100 mL). The or-
ganic layer was washed with brine (100 mL), dried (MgSO4),
and the solvent was removed by rotary evaporation.
0.70, CHCl3). H NMR (400 MHz, CDCl3) d: 1.13 (d, J ¼ 6.4
Hz, 3H), 2.88 (dq, J ¼ 7.4, 6.4 Hz, 1H), 2.95 (s, 3H), 5.19 (d,
J ¼ 7.4 Hz, 1H), 7.36–7.85 (m, 8H), 7.81–7.84 (m, 3H), 8.79
(d, J ¼ 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) d: 14.4,
43.7, 57.4, 82.8, 124.9, 125.7, 126.1, 126.8, 127.5, 128.3,
128.6, 128.7, 129.7, 130.7, 133.9, 137.9, and 147.1. IR (nujol):
1614, 1020, 759, and 706 cmꢁ1. ESI-HRMS calcd. for
C21H21N2O (M þ Hþ): 317.1654. Found: 317.1643.
cis-(5S,6S)-4,5-Dimethyl-2-(1-naphthyl)-6-phenyl-5,6-dihy-
dro-4H-1,3,4-oxadiazine (16). Hydrazide 13 (1.00 g, 3.40
mmol) and a 30% solution of HBr in propanoic acid (15 mL)
were combined in a 100-mL round-bottom flask and this reac-
tion mixture stirred. After 24 h, the reaction was diluted with
H2O (100 mL) and neutralized with NaHCO3. The organic
layer was diluted with EtOAc (100 mL), washed with brine
(50 mL), dried with MgSO4, and the solvents were removed
via rotary evaporation. The title compound was isolated by
flash chromatography (95:5, hexanes:EtOAc). Yellow solid
N0-(1-Benzyl-2-hydroxyethyl)-N0-isopropyl benzoic acid hy-
drazide (20a) The use of benzoic acid afforded the title com-
pound as a yellow solid (55%) contaminated with <5% of ben-
zoic acid: Mp ¼ 126–128ꢀC, [a]D22 ¼ þ27.4 (c 1.24, CHCl3). 1H
NMR (400 MHz, CDCl3): d 1.16 (d, J ¼ 6.6 Hz, 3H) 1.22 (d, J
¼ 6.6 Hz, 3H), 2.53 (m, 1H), 2.91 (d, J ¼ 13.3, 3.9 Hz, 1H),
3.23–3.33 (m, 1H), 3.44–3.50 (m, 1H), 7.05 (s, 1H), 7.13–7.74
(m, 5H). 13C NMR (100 MHz, CDCl3): d 20.6, 32.4, 53.5, 61.3,
63.3, 126.3, 127.1, 128.6, 128.6, 128.9, 131.7, 138.5, and 168.9
ppm. IR (nujol mull): 3203 and 1648 cmꢁ1. ESI-HRMS calcd.
for C19H25N2O2 (M þ Hþ): 313.1916. Found: 313.1909.
1
(21%), Mp ¼ 125–128ꢀC. [a]D23 ¼ ꢁ86.4 (c 0.53, CHCl3). H
N0-(1-Benzyl-2-hydroxyethyl)-N0-isopropyl propanoic acid
hydrazide (20b) The use of propanoic anhydride afforded a
white solid (65%). Mp ¼ 118–120ꢀC, [a]D24 ¼ ꢁ7.28 (c 0.82,
NMR (400 MHz, CDCl3) d (ppm): 0.94, (d, J ¼ 6.6 Hz, 3H),
2.95 (s, 3H), 3.46 (dq, J ¼ 6.6, 3.0 Hz, 1H), 5.65 (d, J ¼ 3.0
Hz, 1H), 7.39–7.53 (m, 8H), 7.84–7.89 (m, 3H), 8.74 (d, J ¼
8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) d (ppm): 8.2, 43.0,
54.8, 79.6, 124.9, 125.7, 126.1, 126.3, 126.5, 126.8, 127.9,
128.3, 129.7, 130.0, 130.8, 133.9, 138.1, and 145.5. IR (nujol):
1
CHCl3). H NMR (400 MHz, CDCl3): d 1.08 (d, J ¼ 6.3 Hz,
3H), 1.14 (d, J ¼ 6.3 Hz, 3H), 1.21 (t, J ¼ 7.4 Hz, 3H), 2.20
(q, J ¼ 7.4 Hz, 2H), 2.38–2.50 (m, 1H), 2.83 (d, J ¼ 13.2, 4.1
Hz, 1H), 3.11–3.23 (m, 2H), 3.33–3.45 (m, 2H), 4.52 (broad
singlet, 1H) 6.26 (s), 7.12–7.32 (m, 5H). 13C NMR (100 MHz,
CDCl3): d 10.1, 20.5, 27.3, 31.7, 52.7, 61.1, 62.8, 126.1,
128.4, 128.7, 138.5, and 175.5 ppm. IR (nujol mull): 3225 and
1666 cmꢁ1. ESI-HRMS calcd. for C15H25N2O2 (M þ Hþ):
265.1916. Found: 265.1921.
1613, 995, 746, and 709 cmꢁ1
. ESI-HRMS calcd. for
C21H21N2O (M þ Hþ): 317.1654. Found: 317.1642.
trans-(5S,6S)-2-Ethyl-4,4-dimethyl-6-phenyl-5,6-dihydro-
4H-1,3,4-oxadiazine (17). Hydrazide 13 (0.25 g, 1.06 mmol)
and H2SO4 (3 mL, 12M) were combined in 100-mL round-bottom
flask and stirred for 24 h. The solution was diluted with H2O (100
mL) and neutralized with NaHCO3. The organic layer was diluted
with EtOAc (100 mL), washed with brine (50 mL), dried with
MgSO4, and the solvents were removed via rotary evaporation.
The title product was isolated by flash column chromatography
(hexanes:EtOAc, 9:1). Yellow oil (64%). [a]2D3 ¼ þ288.8 (c 0.10,
CHCl3). 1H NMR (400 MHz, CDCl3) d: 0.90 (d, J ¼ 6.3 Hz, 3H),
1.1 (t, J ¼ 7.5 Hz, 3H), 2.17 (q, J ¼ 7.5 Hz, 2H), 2.37–2.43 (m,
6.3 Hz, 1H), 2.63, (s, 3H), 4.79 (d, J ¼ 7.8 Hz, 1H), 7.19–7.30
(m, 5H). 13C NMR (100 MHz, CDCl3) d (ppm): 11.1, 14.3, 26.6,
43.5, 57.8, 82.3, 127.4, 128.5, 128.6, 138.0, and 151.9. IR (neat):
N0-(1-Benzyl-2-hydroxyethyl)-N0-isopropyl 1-naphthoic acid
hydrazide (20c) Hydrazine 19 (1.00 g, 4.80 mmol) was com-
bined with dichloromethane (24 mL) and TEA (0.736 mL,
5.28 mmol) and the solution was cooled to 0ꢀC. The reaction
was stirred for 5 min and 1-naphthoyl chloride (0.76 mL, 5.0
mmol) was added by syringe. After 24 h, the reaction was
quenched by the addition of a saturated solution of ammonium
chloride (100 mL) and diluted with CH2Cl2 (100 mL). The
aqueous layer was drawn off and the organic layer was washed
with brine (100 mL), dried (MgSO4), and the solvent was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet