(1S,4R)-1-Isopropylsulfanylmethyl-7,7-dimethyl-bicyclo-
[2.2.1]heptan-2-one oxime (5c). Following the general
procedure, ketone 4c (500 mg, 2.21 mmol) furnished after
purification by flash chromatography (pentane–AcOEt 90 : 10)
481 mg (2.00 mmol, 90%) of 5c as a white solid. Rf 0.52
organic phase was washed with brine (2 × 10 ml), dried over
Na2SO4, filtered and evaporated. The residue was purified by
flash chromatography (CH2Cl2–MeOH 98 : 2) to yield 6a (541
mg, 2.71 mmol, 58%) as a colourless oil. Rf 0.36 (CH2Cl2–
1
MeOH 90 : 10); [α]23 Ϫ76.0 (c 0.81, CHCl3); H NMR (300
D
(pentane–AcOEt 85 : 15); [α]23 Ϫ55.6 (c 0.65, CHCl3);
MHz, CDCl3) δ 0.84 (s, 3H), 1.03 (s, 3H), 1.04–1.17 (m, 1H),
1.21–1.32 (m, 1H), 1.39–1.62 (m, 4H), 1.63–1.79 (m, 3H), 2.15
(s, 3H), 2.50 (d, J = 11.1 Hz, 1H), 2.78 (d, J = 11.1 Hz, 1H),
2.95–3.03 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 17.2, 20.1,
21.1, 27.1, 33.3, 35.0, 39.7, 45.2, 47.9, 51.6, 57.7; MS (EI) m/z
(rel. intensity) 200 ([Mϩ1]ϩ 100), 183 (24), 152 (25); HRMS
(FABϩ) calculated for C11H21NS: 199.1395; found: 200.1475
[MϩH]ϩ.
D
1H NMR (300 MHz, CDCl3) δ 0.86 (s, 3H), 1.00 (s, 3H), 1.27 (d,
J = 6.6 Hz, 3H), 1.28 (d, J = 6.6 Hz, 3H), 1.57–1.68 (m, 1H),
1.78–2.10 (m, 4H), 2.51–2.60 (m, 1H), 2.59 (d, J = 12.0 Hz, 1H),
2.78–2.91 (m, 1H), 2.87 (d, J = 12.0 Hz, 1H), 8.1 (br. s, 1H). 13
C
NMR (75 MHz, CDCl3) δ 19.6, 19.8, 23.3, 27.1, 29.4, 29.7, 32.9,
36.9, 44.1, 49.5, 54.7, 77.2, 168.6; MS (EI) m/z (rel. intensity)
241 (Mϩ, 15), 224 (100), 198 (20), 182 (30), 167 (32), 150 (25),
126 (14); HRMS (FABϩ) calculated for C13H23NOS: 227.1344;
found: 228.1443 [MϩH]ϩ.
(1S,2R,4R)-1-Ethylsulfanylmethyl-7,7-dimethyl-bicyclo-
[2.2.1]heptan-2-ylamine (6b). Following the general procedure,
oxime 5b (533 mg, 2.34 mmol) gave after purification by flash
chromatography (CH2Cl2–MeOH–Et3N 95 : 4 : 1) 294 mg (1.38
(1S,4R)-1-Benzylsulfanylmethyl-7,7-dimethyl-bicyclo[2.2.1]-
heptan-2-one oxime (5d). Following the general procedure,
ketone 4d (500 mg, 1.81 mmol) furnished after purification
by flash chromatography (pentane–AcOEt 95 : 5) 464 mg (1.59
mmol, 59%) of 6b as a colourless oil. [α]23 Ϫ84.6 (c 1.15,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 0.87 (s, 3H), 1.06
(s, 3H), 1.25–1.34 (m, 6H), 1.55–1.62 (m, 3H), 1.69–1.79 (m,
3H), 2.42–2.63 (m, 3H), 2.78–2.83 (d, J = 8.9, 1H), 3.00–3.05
(m, 1H). 13C NMR (75 MHz, CDCl3) δ 14.9, 20.4, 21.4, 27.4,
27.6, 32.1, 33.6, 39.9, 44.4, 45.5, 48.1, 57.9; MS (EI) m/z (rel.
intensity) 214 ([Mϩ1]ϩ 100), 183 (17), 152 (22); HRMS (FABϩ)
calculated for C12H23NS: 213.1551; found 214.1646 [MϩH]ϩ.
mmol, 88%) of 5d as a colourless oil. Rf 0.40 (pentane–AcOEt
1
85 : 15); [α]23 Ϫ24.6 (c 0.41, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 0.82 (s, 3H), 0.89 (s, 3H), 1.15–1.30 (m, 1H), 1.52–1.70
(m, 1H), 1.71–1.90 (m, 3H), 2.03–2.12 (m, 1H), 2.50 (d, J = 12.2
Hz, 1H), 2.52–2.63 (m, 1H), 2.82 (d, J = 12.2 Hz, 1H), 3.73 (d,
J = 3.4 Hz, 2H), 7.16–7.38 (m, 5H), 8.65 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 19.3, 19.7, 27.0, 29.7, 30.4, 32.9, 38.5, 44.1,
49.5, 54.8, 126.9, 128.3, 129.1, 138.4, 168.2; MS (EI) m/z (rel.
intensity) 289 (Mϩ, 3), 198 (100), 150.1 (8), 91 (19); HRMS
(FABϩ) calculated for C17H23NOS: 289.1500; found: 290.1548
[MϩH]ϩ.
(1S,2R,4R)-1-Isopropylsulfanylmethyl-7,7-dimethyl-bicyclo-
[2.2.1]heptan-2-ylamine (6c). Following the general procedure,
oxime 5c (354 mg, 1.46 mmol) gave after purification by flash
chromatography (CH2Cl2–MeOH–Et3N 95 : 4 : 1) 201 mg (0.88
mmol, 61%) of 6c as a colourless oil. [α]23 Ϫ57.4 (c 0.81,
D
1
(1S,4R)-1-Phenylsulfanylmethyl-7,7-dimethyl-bicyclo[2.2.1]-
heptan-2-one oxime (5e). Following the general procedure,
ketone 4e (2 g, 7.68 mmol) furnished after purification by flash
CHCl3); H NMR (300 MHz, CDCl3) δ 0.85 (s, 3H), 1.04 (s,
3H), 1.04–1.17 (m, 1H), 1.19–1.32 (m, 1H), 1.29 (d, J = 6.7 Hz,
3H), 1.30 (d, J = 6.7 Hz, 3H), 1.47–1.62 (4H), 1.63–1.79 (3H),
2.52 (d, J = 10.7 Hz, 1H), 2.77 (d, J = 10.7 Hz, 1H), 2.82–2.92
(m, 1H), 2.93–3.02 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 20.2,
21.1, 23.5, 27.1, 30.2, 33.3, 36.0, 39.5, 45.2, 47.9, 51.0, 57.5. MS
(EI) m/z (rel. intensity) 228 ([Mϩ1]ϩ 100), 152 (50), 107 (33);
HRMS (FABϩ) calculated for C13H25NS: 227.1708; found:
228.1809 [MϩH]ϩ.
chromatography (pentane–AcOEt 95 : 5) 1.87 g (6.84 mmol,
1
89%) of 5e as a white solid. [α]23 Ϫ75.6 (c 1.15, CH2Cl2); H
D
NMR (400 MHz, CDCl3) δ 0.92 (s, 3H), 1.04 (s, 3H), 1.25–1.36
(m, 1H), 1.69–1.77 (m, 1H), 1.85–2.05 (m, 3H), 1.06–1.13 (d,
J = 17.6 Hz, 1H), 2.57–2.66 (m, 1H), 2.98–3.04 (d, J = 12 Hz,
1H), 2.33–2.39 (d, J = 12 Hz, 1H), 7.14–7-19 (m, 1H), 7.25–7.31
(m, 2H), 7.35–7.45 (m, 3H). 13C NMR (100 MHz, CDCl3)
δ 19.8, 20.0, 27.4, 30.0, 33.1, 33.3, 44.4, 49.9, 55.2, 125.8 (2C),
123.0 (3C), 139.5, 168.8; MS (EI) m/z (rel. intensity) 276 (Mϩ,
50), 258 (100); HRMS (FABϩ) calculated for C16H21NOS:
275.1344; found: 276.1462 [MϩH]ϩ.
(1S,2R,4R)-1-Benzylsulfanylmethyl-7,7-dimethyl-bicyclo-
[2.2.1]heptan-2-ylamine (6d). Following the general procedure,
oxime 5d (351 mg, 1.20 mmol) furnished after purification by
flash chromatography (CH2Cl2–MeOH–Et3N 95 : 4 : 1) 170 mg
(0.61 mmol, 51%) of 6d as a colourless oil. 1H NMR (400 MHz,
CDCl3) δ 0.803 (s, 3H), 0.972 (s, 3H), 1.02–1.11 (m, 2H), 1.17–
1.34 (m, 2H), 1.45–1.57 (m, 2H), 1.63–1.79 (m, 3H), 2.45–2.51
(d, J = 11.2 Hz, 1H), 2.64–2.70 (d, J = 11.2 Hz, 1H), 7.22–7.27
(m, 1H), 7.29–7.39 (m, 4H). 13C NMR (100 MHz, CDCl3)
δ 20.4, 21.4, 27.3, 31.8, 33.5, 38.0, 39.9, 45.4, 48.1, 51.5, 57.9,
127.2, 128.7, 129.0; MS (EI) m/z (rel. intensity) 276 ([Mϩ1]ϩ
100), 184 (46), 152 (40), 91 (41); calculated for C17H25NS:
275.1708; found: 276.1788 [MϩH]ϩ.
(1S,4R)-1-Mercaptomethyl-7,7-dimethyl-bicyclo[2.2.1]-
heptan-2-one oxime (5f ). Following the general procedure,
ketone 3 (2 g, 10.80 mmol) furnished after purification by flash
chromatography (pentane–AcOEt 90 : 10) 2.02 g (10.15 mmol,
94%) of 5f as a white solid. 1H NMR (400 MHz, CDCl3) δ 0.86
(s, 3H), 0.97 (s, 3H), 1.22–1.34 (m, 1H), 1.75–1.98 (m, 6H),
2.01–2.09 (d, J = 17.6 Hz, 1H), 2.42–2.50 (m, 1H), 2.53–2.62
(m, 1H), 2.85–2.96 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 19.78, 20.01, 27.35, 28.69, 30.02, 31.20, 33.12, 44.41, 49.72,
167.56; HRMS (FABϩ) calculated for C10H17NOS: 199.1031;
found: 200.1112 [MϩH]ϩ.
(1S,2R,4R)-1-Methylsulfanylmethyl-7,7-dimethyl-bicyclo-
[2.2.1]heptan-2-ylmethylamine 8a20. A solution of 6a (181 mg,
0.91 mmol) and formamide (250 µl, 12.8 mmol, 7 equiv.) was
heated at 120 ЊC for 15 min, then poured on water (2 ml) and
extracted with CH2Cl2 (3 × 20 ml) to yield 197 mg (0.87 mmol,
96%) of a colourless oil. This crude product was dissolved in
THF (5 ml) and added to a suspension of LiAlH4 (33 mg, 0.87
mmol) in THF (5 ml). The mixture was refluxed overnight and
cooled. 33 µl of H2O, 33 µl of a 15% NaOH solution and 100 µl
of H2O were sequentially added, the resulting suspension was
filtered and the solution was washed with ether. After evapor-
ation of the solvents, the residue was purified by flash chroma-
tography (CH2Cl2–MeOH–Et3N 92 : 7 : 1) to afford 164 mg
(0.77 mmol, 88%) of 8a as a colourless oil. [α]23D Ϫ109.1 (c 0.83,
General procedure for the reduction of oxime with NaBH4–
19
NiCl2
(1S,2R,4R)-1-Methylsulfanylmethyl-7,7-dimethyl-bicyclo-
[2.2.1]heptan-2-ylamine (6a). To a solution of the oxime 5a
(1.00 g, 4.69 mmol) and NiCl2 (1.21 g, 9.83 mmol, 2 equiv.) in
methanol (60 ml), at Ϫ30 ЊC, NaBH4 (1.77 g, 46.9 mmol, 10
equiv.) was added in portions over 1 hour. The reaction mixture
was further stirred for 1 hour at Ϫ30 ЊC, and 2 hours at room
temperature. After evaporation of the solvent, a 3 M NaOH
solution (8 ml) was added followed by ether (50 ml) and the
suspension was filtered. The phases were separated and the
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 8 7 – 1 8 9 3
1891