A. M. Gil et al. / Tetrahedron: Asymmetry 16 (2005) 3115–3123
3121
(76.6 mg, 0.24 mmol). Colourless oil. [a]D = ꢀ90.0 (c
hexane/ethyl acetate as an eluent, supplied the cyano-
methyl derivative 12 in 76% yield (63.0 mg, 0.22 mmol).
Colourless oil. [a]D = ꢀ60.2 (c 0.3, CHCl3). IR(nujol)
m (cmꢀ1): 3060–2854, 2246, 1745, 1648; 1H NMR
(CDCl3) d (ppm): 7.70–7.68 (m, 2H), 7.54–7.49 (m,
1H), 7.44–7.40 (m, 2H), 4.28 (dd, 1H, J = 4.8 Hz,
J = 4.8 Hz), 3.81 (s, 3H), 2.96 (dd, 1H, J = 16.2 Hz,
J = 4.8 Hz), 2.54–2.40 (m, 3H), 2.01 (dd, 1H,
J = 12.7 Hz, J = 8.2 Hz), 1.88–1.72 (m, 3H), 1.59–1.52
(m, 2H); 13C NMR(CDCl 3) d (ppm): 173.3, 169.6,
134.0, 132.0, 128.7, 128.5, 118.7, 69.1, 61.6, 52.4, 42.1,
38.0, 32.1, 30.1, 22.1.
1
0.4, CHCl3). IR(neat) m (cmꢀ1): 1738, 1651; H NMR
(CDCl3) d (ppm): 7.71–7.65 (m, 2H), 7.45–7.44 (m,
1H), 7.42–7.34 (m, 2H), 4.18 (dd, 1H, J = 4.4 Hz,
J = 4.4 Hz), 3.76 (s, 3H), 2.87 (dd, 1H, J = 12.9 Hz,
J = 5.2 Hz), 2.51–2.34 (m, 2H), 2.29–2.18 (m, 1H),
2.06 (s, 3H), 1.89–1.70 (m, 4H), 1.54–1.43 (m, 1H); 13C
NMR(CDCl 3) d (ppm): 173.9, 170.3, 134.5, 131.7,
128.8, 128.3, 70.2, 62.0, 52.1, 45.7, 38.5, 37.8, 31.3,
30.4, 15.4.
4.10. Methyl (1S,2R,4R)-N-benzoyl-2-benzylthiomethyl-
7-azabicyclo[2.2.1]heptane-1-carboxylate, 11
4.12. Methyl (1S,2S,4R)-N-benzoyl-2-azidomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 13
Over a suspension of NaH (13.0 mg, 0.54 mmol) in dry
DMF (5 mL) under argon atmosphere was slowly added
benzylmercaptane (67.0 mg, 0.54 mmol) and the mixture
stirred at room temperature for one hour. Then, a solu-
tion of methyl (1S,2R,4R)-N-benzoyl-2-bromomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate 6 (100 mg, 0.27
mmol) in dry DMF (2 mL) was added and the resulting
solution heated at 60 ꢁC for 3 h under an argon atmo-
sphere. Then, the reaction mixture was allowed to cool
down to room temperature and the solvent evaporated
under vacuum. The resulting crude mixture was
dissolved in a water/dichloromethane mixture. The
aqueous layer was washed with dichloromethane
(3 · 10 mL), the combined organic layers were dried
over anhydrous magnesium sulfate, filtered and the
solvent was removed under vacuum. A column chroma-
tography, using a 7:3 mixture of hexane/ethyl acetate,
provided the thioether derivative 11 in 77% yield
(85.2 mg, 0.22 mmol). Colourless oil. [a]D = ꢀ75.1 (c
Sodium azide (36.4 mg, 0.56 mmol) was added over a
solution of methyl (1S,2R,4R)-N-benzoyl-2-bromo-
methyl-7-azabicyclo[2.2.1]heptane-1-carboxylate 6 (100
mg, 0.28 mmol) in dry DMF (5 mL) under an argon
atmosphere and the mixture heated at 90 ꢁC for 5 h.
Then, the solvent was evaporated under vacuum, the
residue redissolved in dichloromethane (100 mL), and
washed with water (3 · 50 mL). The organic layer was
dried over anhydrous magnesium sulfate, filtered and
the solvent eliminated under vacuum. The residue was
purified by column chromatography (eluent: 6:4 hex-
ane/ethyl acetate). The product was obtained in this
way as a white solid in 92% yield (81.0 mg, 0.26 mmol).
White solid. Mp 115 ꢁC. [a]D = ꢀ62.3 (c 0.5, CHCl3). IR
1
(nujol) m (cmꢀ1): 2093, 1737, 1646; H NMR(CDCl ) d
3
(ppm): 7.74–7.66 (m, 2H), 7.55–7.36 (m, 3H), 4.22 (dd,
1H, J = 4.8 Hz, J = 4.4 Hz), 3.83 (s, 3H), 3.78–3.70
(m, 1H), 3.27 (dd, 1H, J = 12.5 Hz, J = 8.1 Hz), 2.50–
2.36 (m, 1H), 2.33–2.19 (m, 1H), 1.90–1.66 (m, 4H),
0.5, CHCl3). IR(neat) m (cmꢀ1): 3059–2874, 1737,
1
1656; H NMR(CDCl ) d (ppm): 7.60–7.57 (m, 2H),
1.59–1.47 (m, 1H). 13C NMR(CDCl ) d (ppm): 173.7,
3
3
7.43–7.39 (m, 1H), 7.33–7.30 (m, 2H), 7.27–7.20 (m,
4H), 7.19–7.15 (m, 1H), 4.07 (dd, 1H, J = 4.8 Hz,
J = 4.5 Hz), 3.66 (s, 3H), 3.62 (s, 2H), 2.77 (dd, 1H,
J = 12.8 Hz, J = 5.2 Hz), 2.36–2.28 (m, 2H), 2.02–2.01
(m, 1H), 1.74–1.53 (m, 4H), 1.42–1.35 (m, 1H); 13C
NMR(CDCl 3) d (ppm): 173.8, 170.1, 138.3, 134.4,
131.6, 128.8, 128.7, 128.4, 128.2, 126.9, 70.1, 62.0,
51.9, 45.9, 37.7, 36.3, 35.7, 31.0, 30.3.
169.9, 134.2, 131.8, 128.7, 128.3, 77.2, 68.9, 61.7, 54.0,
52.3, 45.8, 35.8, 31.1, 30.3. Anal. Calcd for
C16H18N4O3: C, 61.13; H, 5.77; N, 17.82. Found: C,
61.20; H, 5.68; N, 17.67.
4.13. Methyl (1S,2S,4R)-N-benzoyl-2-aminomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 15
To a solution of methyl (1S,2S,4R)-N-benzoyl-2-azi-
domethyl-7-azabicyclo[2.2.1]heptane-1-carboxylate 13
(100 mg, 0.32 mmol) in dry methanol (10 mL), 10%
Pd/C (20 mg) was added and the resulting suspension
heated at 30 ꢁC under hydrogen atmosphere for 3 h.
The catalyst was then filtered off through a Celite pad,
which was washed with dichloromethane. The solvent
was evaporated under vacuum until dryness. This proce-
dure supplied the unstable amino derivative in pure
4.11. Methyl (1S,2S,4R)-N-benzoyl-2-cyanomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 12
To a suspension of potassium cyanide (91.2 mg,
1.4 mmol) and a catalytic quantity of 18-crown-6 ether
in dry DMF (2 mL) under argon atmosphere, a solution
of methyl (1S,2R,4R)-N-benzoyl-2-bromomethyl-7-aza-
bicyclo[2.2.1]heptane-1-carboxylate
6 (100 mg, 0.28
mmol) in dry DMF (2 mL) was added. The mixture
was heated at 80 ꢁC for one day and, then, it was al-
lowed to cool down to room temperature and the sol-
vent was evaporated under vacuum. The resulting
crude mixture was dissolved in a water/dichloromethane
mixture. The aqueous layer was washed with dichloro-
methane (3 · 10 mL), the combined organic layers dried
over anhydrous magnesium sulfate, filtered and the sol-
vent was removed under vacuum. The column chroma-
tography of the resulting oil, using a 1:1 mixture of
NMRspectroscopic form. 1H NMR(CDCl ) d (ppm):
3
7.77–7.67 (m, 2H), 7.50–7.44 (m, 1H), 7.41–7.35
(m, 2H), 4.17 (dd, 1H, J = 4.8 Hz, J = 4.4 Hz), 3.78
(s, 3H), 2.94 (dd, 1H, J = 12.9 Hz, J = 6.2 Hz), 2.65
(dd, 1H, J = 12.9 Hz, J = 6.6 Hz), 2.40 (ddd, 1H,
J = 12.5 Hz, J = 12.1 Hz, J = 4.6 Hz), 2.14–2.03
(m, 1H), 1.86–1.59 (m, 4H), 1.54–1.45 (m, 3H). 13C
NMR(CDCl 3) d (ppm): 173.7, 170.8, 134.7, 131.6,
128.8, 128.3, 69.5, 62.0, 51.9, 50.1, 44.8, 35.1, 31.1,
30.6.