M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 2471–2478
2477
4.8 Hz, 1H), 3.42–3.48 (m, 1H), 3.86 (s, 3H), 4.01 (dd, J = 10.4,
2.7 Hz, 1H), 4.14 (dd, J = 10.4, 4.0 Hz, 1H), 6.97–7.43 (m, 7H),
7.80–7.82 (m, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d: 16.2, 18.3,
20.7, 34.5, 52.6, 53.6, 61.0, 66.0, 123.5, 126.5, 127.1, 127.9, 128.6,
129.3, 131.8, 138.1, 144.1, 156.4 ppm. IR (neat): 1686, 1448,
1213 cmꢀ1. ESI-HRMS calcd for C21H27N2O2 (M+H+): 339.2073.
Found: 339.2072.
124.9, 125.1, 126.8, 127.1, 127.3, 128.7, 129.3, 134.7, 137.3,
148.3, 154.6 ppm. IR (neat): 3490, 1618, 1456 cmꢀ1. ESI-HRMS
calcd for C23H25N2O2 (M+H+): 361.1802. Found: 361.1816.
4.16.2. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-
oxadiazin-2-yl)-6-tert-butylphenol 22c
In
a flame dried, nitrogen purged flask 21c (0.211 g,
0.555 mmol) and CH2Cl2 (5 mL) were placed. The reaction mixture
was cooled to 0 °C before the dropwise addition of 1 M BBr3 in tol-
uene (1.0 mL, 1.0 mmol). The reaction mixture was stirred over-
night and then quenched with H2O (50 mL). The organic layer
was extracted with ether (2 ꢁ 50 mL) and washed with brine
(50 mL). The organic layer was dried over MgSO4 and the solvent
was removed by rotary evaporation. The title compound was iso-
lated by flash column chromatography (hexanes/EtOAc, 98:2). Yel-
4.15.2. (S)-5-Benzyl-4-isopropyl-2-(1-methoxynaphthalen-2-
yl)-5,6-dihydro-4H-1,3,4-oxadiazine 21b
Yellow oil (24%).
½
a 2D4
ꢂ
¼ þ191:3 (c 1.21, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 1.17 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.4 Hz,
3H), 2.78 (dd, J = 13.5, 9.8 Hz, 1H), 3.05 (dd, J = 13.5, 4.8 Hz, 1H),
3.45–3.51 (m, 1H), 4.01 (s, 3H), 4.05 (dd, J = 10.3, 2.8 Hz, 1H),
4.20 (dd, J = 10.3, 4.2 Hz, 1H), 7.20–7.33 (m, 1H), 7.42–7.49
(m, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.79–7.87
(m, 1H), 8.20–8.22 (m, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d:
18.3, 20.9, 34.8, 52.7, 53.8, 62.6, 66.2, 121.8, 122.8, 123.3, 125.9,
126.5, 126.6, 127.6, 128.5, 128.7, 129.3, 135.0, 138.0, 143.8,
154.3 ppm. IR (neat): 1686, 1448, 1213 cmꢀ1. ESI-HRMS calcd for
low oil (54%). ½a D24
ꢂ
¼ þ146:9 (c 1.03, CHCl3). 1H NMR (400 MHz,
CDCl3) d (ppm): 1.15 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H),
1.44 (s, 3H), 2.69 (dd, J = 13.6, 9.7 Hz, 1H), 3.04 (dd, J = 13.6,
5.0 Hz, 1H), 3.42–3.52 (m. 1H), 4.04 (dd, J = 10.4, 2.8 Hz, 1H), 4.15
(dd, J = 10.4, 4.6 Hz, 1H), 6.77 (t, J = 4.2 Hz, 1H), 7.19–7.29 (m,
7H), 7.49 (dd, J = 7.9, 1.75 Hz, 1H), 12.3 (s, 1H). 13C NMR (CDCl3,
100 MHz) d (ppm): 17.5, 21.0, 29.5, 34.5, 34.9, 52.3, 53.9, 66.4,
114.8, 117.4, 123.5, 126.7, 127.7, 128.7, 129.3, 136.7, 137.4,
147.8, 156.7. IR (neat): 3489, 1617, 1443 cmꢀ1. ESI-HRMS calcd
for C23H31N2O2 (M+H+): 367.2318. Found: 367.2314.
C
24H27N2O2 (M+H+): 375.2073. Found: 375.2066.
4.15.3. (S)-5-Benzyl-2-(3-tert-butyl-2-methoxyphenyl)-4-
isopropyl-5,6-dihydro-4H-1,3,4-oxadiazine 21c
Yellow oil (13%).
½
a 2D4
ꢂ
¼ þ156:1 (c 1.11, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 1.13 (d, J = 6.4 Hz, 3H), 1.30 (d, J = 6.4 Hz,
3H), 1.38 (s, 9H), 2.70 (dd, J = 13.5, 9.8 Hz, 1H), 3.05 (dd, J = 13.5,
4.8, 1H), 3.40–3.53 (m, 2H), 3.84 (s, 3H), 4.03 (dd, J = 11.4, 2.8 Hz,
1H), 4.18 (dd, J = 10.4, 4.8 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 7.20–
7.41 (m, 7H) ppm. 13C NMR (CDCl3, 100 MHz) d: 17.9, 20.6, 30.8,
35.1, 35.3, 52.4, 53.5, 60.7, 66.4, 122.5, 126.6, 127.0, 127.8, 128.6,
129.4, 129.5, 137.9, 142.8, 145.1, 158.0 ppm. IR (neat): 1686,
4.17. General procedure for the diethylzinc addition with
aldehydes
A chiral ligand of choice (0.313 mmol) was added to a flame
dried round bottomed flask with toluene (4.1 mL) in an inert atmo-
sphere. To the flask was added a solution of diethylzinc in hexanes
(1 M, 9.4 mL) and the mixture was allowed to stir at room temper-
ature for 25 min. An aldehyde of choice (3.13 mmol) was then
added and allowed to stir at room temperature for 24 h. The reac-
tion was quenched with HCl (1 M, 50 mL) and extracted with
CH2Cl2 (2 ꢁ 50 mL). The organic solution was washed with brine,
dried over (MgSO4), gravity filtered, and concentrated under re-
duced pressure to afford enantiomerically enriched alcohol. The
enantioselectivity of this process was immediately determined by
chiral stationary phase HPLC.
1448, 1213 cmꢀ1
.
ESI-HRMS calcd for C24H33N2O2 (M+H+):
381.2542. Found: 381.2537.
4.16. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-
oxadiazin-2-yl)-6-methylphenol 22a
In a flame dried, nitrogen purged flask were placed 21a (1.10 g,
3.25 mmol) and CH2Cl2 (32 mL). The reaction mixture was cooled
to 0 °C before the dropwise addition of 1 M BBr3 in toluene
(5.5 mL, 5.5 mmol). The reaction mixture was stirred overnight
and then quenched with H2O (75 mL). The organic layer was ex-
tracted with ether (2 ꢁ 50 mL) and washed with brine (50 mL).
The organic layer was dried over MgSO4 and the solvent was re-
moved by rotary evaporation. The title compound was isolated
by flash column chromatography (hexanes/EtOAc, 95:5). See 13b
for characterization data.
Acknowledgments
The authors acknowledge support for this work by the donors of
the Petroleum Research Fund as administered by the American
Chemical Society (PRF 48367-B1).
References
4.16.1. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-
oxadiazin-2-yl)naphthalen-1-ol 22b
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In
a flame dried, nitrogen purged flask 21b (0.147 g,
0.376 mmol) and CH2Cl2 (5 mL) were placed. The reaction mixture
was cooled to 0 °C before the dropwise addition of 1 M BBr3 in tol-
uene (0.65 mL, 0.64 mmol). The reaction mixture was stirred over-
night and then quenched with H2O (50 mL). The organic layer was
extracted with ether (2 ꢁ 50 mL) and washed with brine (50 mL).
The organic layer was dried over MgSO4 and the solvent was re-
moved by rotary evaporation. The title compound was isolated
by flash column chromatography (hexanes/EtOAc, 98:2). Yellow
oil (74%). ½a 2D4
ꢂ
¼ þ176:6 (c 0.89, CHCl3). 1H NMR (400 MHz, CDCl3)
d: 1.22 (d, J = 6.4 Hz, 3H), 1.48 (d, J = 6.4 Hz, 3H), 2.73 (dd,
J = 13.6 Hz, 9.6 Hz, 1H), 3.12, (dd, J = 13.6, 5.0 Hz, 1H), 3.49–3.59
(m, 1H), 4.20 (dq, J = 10.4, 5.0 Hz, 1H), 7.26–7.80 (m, 9H), 8.41–
8.43 (m, 1H), 13.01 (s, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d:
17.2, 21.1, 34.5, 52.0, 53.9, 66.9, 107.99, 117.8, 122.0, 123.0,
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