mmol) in THF (5 mL) was added NaH (0.09 g, 2 equiv, 60%
dispersion in oil), and the resulting suspension was stirred for 30
min at room temperature. Subsequently, allyl bromide (0.20 g, 1.05
equiv) was added at 0 °C, followed by reflux for 3 h. Extraction
with water (10 mL) and Et2O (3 × 10 mL), drying (MgSO4),
filtration of the drying agent, and removal of the solvent in vacuo
afforded 1-tert-butyl-2-(allyloxymethyl)aziridine 4, which was
filtered through a pad of silica (hexane/EtOAc, 5/4) to obtain an
4-tert-Butyl-3,5-di(cyanomethyl)morpholine 9. To a solution
of 3,5-di(bromomethyl)-4-tert-butylmorpholine 5 (0.1 g, 0.3 mmol)
in DMSO (2 mL) was added KCN (0.06 g, 3 equiv), and the mixture
was heated at 60 °C for 3 h. Extraction with water (5 mL) and
Et2O (3 × 5 mL), washing of the organic extracts with brine (2 ×
5 mL), drying (MgSO4), filtration of the drying agent, and removal
of the solvent in vacuo afforded 4-tert-Butyl-3,5-di(cyanomethyl)-
morpholine 9, which was purified by flash chromatography on silica
gel (hexane/EtOAc, 5/4). Yield 77% of colorless crystals, mp 92.2-
1
analytically pure sample. Yield 89% of light-yellow oil. H NMR
(300 MHz, CDCl3): δ 0.99 (9H, s); 1.41 (1H, d, J ) 3.3 Hz); 1.58
(1H, d, J ) 6.3 Hz); 1.83-1.93 (1H, m); 3.35 and 3.43 (2H, 2 ×
d × d, J ) 10.2, 6.1, 5.8 Hz); 3.96-4.08 (2H, m); 5.15-5.32 (2H,
m); 5.86-5.98 (1H, m). 13C NMR (75 MHz, CDCl3): δ 25.2, 26.5,
31.0, 52.7, 72.0, 73.4, 116.8, 134.9. IR (NaCl, cm-1): νmax 3044,
2968, 2928, 2857, 1647, 1363, 1099. MS (70 eV, %): m/z 170
(M+ + 1, 100). Anal. Calcd for C10H19NO: C, 70.96; H, 11.31; N,
8.28. Found: C, 71.13; H, 11.45; N, 8.10. Rf ) 0.27, hexane/EtOAc,
5/4.
1
92.8 °C. H NMR (300 MHz, CDCl3): δ 1.23 (9H, s); 2.62 and
2.67 (4H, 2 × d × d, J ) 16.7, 8.3, 7.4 Hz); 3.40-3.50 (4H, m);
3.84 (2H, d, J ) 11.3 Hz). 13C NMR (75 MHz, CDCl3): δ 24.8,
28.9, 47.0, 56.6, 68.7, 118.4. IR (NaCl, cm-1): νCN 2254. MS (70
eV, %): m/z 221 (M+, 6); 206 (45); 181 (23); 165 (7); 125 (100);
84 (37); 57 (38). Anal. Calcd for C12H19N3O: C, 65.13; H, 8.65;
N, 18.99. Found: C, 65.34; H, 8.83; N, 18.84. Rf ) 0.34, hexane/
EtOAc, 5/4.
cis-3,5-Di(bromomethyl)-4-tert-butylmorpholine 5. To an ice-
cooled solution of 1-tert-butyl-2-(allyloxymethyl)aziridine 4 (0.17
g, 1 mmol) in CH2Cl2 (5 mL), was added dropwise bromine (0.17
g, 1.05 equiv) in CH2Cl2 (2.5 mL), and the resulting solution was
stirred for 3 h at room temperature. Evaporation of the solvent
afforded 3,5-di(bromomethyl)-4-tert-butylmorpholine 5, which was
purified by means of column chromatography on silica gel (hexane/
EtOAc 9/1). Yield 88% (crude), 43% (after column chromatogra-
phy) of colorless crystals, mp 58.4-59.2 °C. 1H NMR (300 MHz,
CDCl3): δ 1.17 (9H, s); 3.10-3.18 (4H, m); 3.29-3.33 (2H, m);
3.45-3.53 (2H, m); 4.22 (2H, d, J ) 11.6 Hz). 13C NMR (75 MHz,
CDCl3): δ 28.9, 35.7, 51.3, 56.2, 66.7. IR (NaCl, cm-1): νmax 2970,
1462, 1368, 1204, 1141, 1043, 899. HRMS calcd for C10H19Br2-
NO, 326.9828/328.9807/330.9787; found, 326.9830/328.9808/
330.9790 (M+, 100). Anal. Calcd for C10H19Br2NO: C, 36.50; H,
5.82; N, 4.26. Found: C, 36.66; H, 5.94; N, 4.18. Rf ) 0.36, hexane/
EtOAc, 9/1.
4-tert-Butyl-3,5-di(methoxymethyl)morpholine 8. To 3,5-di-
(bromomethyl)-4-tert-butylmorpholine 5 (0.1 g, 0.3 mmol) was
added NaOMe (0.45 mL, 3 equiv, 2 N in MeOH), and the mixture
was heated at reflux for 2 h. Extraction with water (5 mL) and
CH2Cl2 (3 × 5 mL), drying (MgSO4), filtration of the drying agent,
and removal of the solvent in vacuo afforded 4-tert-Butyl-3,5-di-
(methoxymethyl)morpholine 8, which was purified by flash chro-
matography on silica gel (hexane/EtOAc, 9/1). Yield 92% of
colorless crystals, mp 34.4-35.0 °C. 1H NMR (300 MHz,
CDCl3): δ 1.14 (9H, s); 2.91-2.98, 3.06-3.10 and 3.28-3.45 (2H,
2H and 4H); 3.34 (6H, s); 3.94 (2H, d, J ) 11.3 Hz). 13C NMR
(75 MHz, CDCl3): δ 28.8, 48.6, 55.9, 58.8, 67.1, 75.6. IR (NaCl,
cm-1): νmax 2974, 2925, 2893, 2853, 1460, 1117, 1097. MS (70
eV, %): m/z 231 (M+, 1); 216 (10); 186 (84); 130 (100); 98 (37);
68 (24); 57 (17). Anal. Calcd for C12H25NO3: C, 62.30; H, 10.89;
N, 6.05. Found: C, 62.49; H, 11.03; N, 5.88. Rf ) 0.08, hexane/
EtOAc, 9/1.
9-(2,2-Dimethylpropyl)-3-oxa-7-thia-9-azabicyclo[3.3.1]no-
nane 15. To a solution of lithium sulfide (80 mg, 1.75 mmol, 5
equiv) in absolute EtOH (60 mL) was added via a syringe a solution
of 4-(2,2-dimethylpropyl)-3,5-di(bromomethyl)morpholine 12g (120
mg, 0,35 mmol) in EtOH (20 mL) under nitrogen atmosphere. The
resulting mixture was heated under reflux for 5 h. Extraction with
water (80 mL) and Et2O (3 × 40 mL), drying (MgSO4), filtration
of the drying agent, and removal of the solvent in vacuo afforded
9-(2,2-dimethylpropyl)-3-oxa-7-thia-9-azabicyclo[3.3.1]nonane 15,
which was filtered through a pad of silica gel to obtain an
analytically pure sample (hexane/EtOAc, 2/3) after crystallization
from EtOH. Yield 91% of colorless crystals, mp 42.6-43.0 °C.
1H NMR (300 MHz, CDCl3): δ 0.84 (9H, s); 2.17-2.31 (2H, m);
2.38 (2H, s); 2.66 (2H, br s); 3.41 (2H, d × d × d, J ) 13.3, 3.7,
2.2 Hz); 3.91-3.95 and 4.04-4.10 (4H, 2 × m). 13C NMR (75
MHz, CDCl3): δ 27.2, 29.4, 34.0, 53.0, 65.5, 69.3. IR (NaCl, in
CDCl3, cm-1): νmax 2951, 2924, 2853, 1479, 1459, 1359, 1180,
1089, 965. MS (70 eV, %): m/z 215 (M+; 9); 200 (4); 158 (100);
128 (3); 112 (5); 73 (5); 56 (4). Anal. Calcd for C11H21NOS: C,
61.35; H, 9.83; N, 6.50. Found: C, 61.54; H, 9.97; N, 6.41.
Acknowledgment. The authors are indebted to the “Fund
for Scientific Research - Flanders (Belgium)” (F.W.O.-Vlaan-
deren) and to Ghent University (GOA) for financial support.
Supporting Information Available: General information and
all spectroscopic data of compounds 10f,g, 11a-g, 12a,d,e,g, and
14d,g. Crystallographic data of compound 5. This material is
JO060313Y
J. Org. Chem, Vol. 71, No. 12, 2006 4681