Helvetica Chimica Acta Vol. 87 (2004)
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blue color appeared and a crystalline precipitate formed (after ca. 1.25 h). The soln. was purged with N2 while
maintaining the low temp. until the blue color disappeared. Dimethyl sulfide (11 ml) and then NaBH4 (4.5 g,
0.12 mol) were added in portions under N2. After the addition, the cooling bath was removed, and the mixture
was stirred for 1 h. Solvents were evaporated, and the residue was washed with H2O and CH2Cl2, collected, and
dried to constant weight. Recrystallization of the solid gave 5 (6.82 g, 82%). M.p. 158 1618. (MeOH/AcOEt
1:2). IR: 3305, 3280 (NÀH, OÀH), 2951 (CÀH), 1695, 1630 (CO). 1H-NMR ((D5)pyridine): 1.87 2.40 (m,
8 H); 3.02 (m, 1 H); 3.67 (s, 3 H); 3.88 (m, 4 H); 4.59 (m, 1 H); 4.71 (d, J 5.4, 2 H); 5.21 (s, OH); 7.18 7.33 (m,
3 H); 7.52 (d, J 7.5, 2 H); 8.22 (d, J 9.0, 1 H); 9.53 (t, J 6.0, 1 H). 13C-NMR: 27.02 (t); 30.06 (t); 30.26 (t);
31.62 (t); 43.12 (t); 51.43 (q); 52.66 (d); 54.00 (d); 61.73 (t); 61.80 (t); 126.94 (d); 127.89 (2C, d); 128.50 (2C, d);
.
140.05 (s); 157.83 (s); 174.25 (s). EI-MS: 352 (3, M ), 207 (44), 162 (112), 132 (110), 106 (82), 105 (88), 91
.
(99), 90 (77), 76 (54). HR-MS: 352.1995 (C18 H28N2O5 ; calc. 352.1997).
2-(1-Benzyl-2-oxopiperidin-3-yl)pyrrolidine-1-carboxylic Acid Methyl Ester (6). To a soln. of 5 (3.05 g,
8.7 mmol) and Et3N (1.93 g, 19 mmol) in anh. THF (80 ml), a soln. of TsCl (4.12 g, 22 mmol) in THF (20 ml) was
added dropwise within 15 min at 08. The mixture was warmed to r. t. while stirring for 3 h, and then brought to
reflux for 6 h. After cooling, the solvent was evaporated, and the residue was dissolved in CH2Cl2 (70 ml). The
soln. was washed twice with sat. NaHCO3 soln. and brine, dried (Na2SO4) and evaporated: mixture of ditosylate
and partially cyclized product (3.82 g) (by NMR). This residue was dissolved in anh. THF (70 ml), the soln.
cooled to 08, and NaH (1.73 g, 60% dispersion in mineral oil, 43.5 mmol) added under N2. After 20 min, the
cooling bath was removed and the mixture refluxed for 7 h. After cooling, the mixture was partitioned between
CH2Cl2 (70 ml) and H2O (100 ml), the aq. phase extracted with more CH2Cl2 (2 Â 30 ml), the combined org.
phase washed with brine, dried (Na2SO4) and evaporated, and the the residue subjected to CC (silica gel, 30%
AcOEt/hexane): 6 (1.46 g, 53% over 2 steps), 1 :1 mixture of the erythro-and threo-isomers. IR: 2948, 2871
(CÀH), 1694, 1627 (CO). 1H-NMR: 1.50 1.78 (m, 8 H); 2.06 (m, 1 H); 3.09 (m, 2 H); 3.20 (m, 1 H); 3.31 (m,
1 H); 3.59 (s, 3 H); 4.49 (br., 2 H); 4.57 (m, 1 H); 7.13 7.24 (m, 5 H). 13C-NMR: 21.76 (t); 21.88 (t); 23.55, 23.97
(2t, 2 isomers); 27.41, 28.07 (2t, 2 isomers); 42.98, 44.36 (2d, 2 isomers); 46.97 (t); 49.75 (t); 51.80, 52.07 (2q, 2
isomers); 57.46, 58.06 (2d, 2 isomers); 126.94 (d); 127.68 (2C, d); 128.24 (2C, d); 137.17 (s); 155.50 (s); 170.36,
.
170.65 (2s, 2 isomers). EI-MS: 316 (47, M ), 257 (68), 189 (100), 160 (13), 159 (16), 128 (76), 128 (75), 91 (90),
.
82 (15). HR-MS: 316.1787 (C18H24N2O3 ; calc. 316.1787).
N-Benzylhexahydronicotine ( 1-Benzyl-3-(1-methylpyrrolidin-2-yl)piperidine; 7). A soln. of 6 (0.3 g,
0.95 mmol) in anh. THF (3 ml) was added dropwise to a stirred suspension of LiAlH4 (0.18 g, 4.72 mmol) in
THF (7 ml) under N2. The mixture was refluxed for 12 h, cooled, and quenched with wet THF, then with H2O.
Addition of 1n NaOH (5 ml) led to a precipitate that was filtered. The filter cake was washed with THF and
MeOH (10 ml each), and the org. solns were combined and evaporated. The residue was partitioned between
H2O (15 ml) and CH2Cl2 (3 Â 10 ml), and usual workup led to 7 (0.24 g).
Hexahydronicotine ( 3-(1-Methylpyrrolidin-2-yl)piperidine; 8). Compound 7 (0.24 g) was debenzylated
under hydrogenolysis conditions. The crude product was percolated through a SiO2 column with 40% AcOEt/
hexane: 8 (0.14 g).
Nicotyrine ( 3-(1-Methyl-1H-pyrrol-2-yl)pyridine; 9). A soln. of 7 (0.11 g, 0.33 mmol) in CH2Cl2 (2 ml)
was added dropwise to Se powder (0.47 g, 5.9 mmol). The solvent was carefully evaporated and the mixture was
heated at 250 2608 for 30 h under N2. The mixture was cooled and the residue scratched off from the flask,
smashed to a fine powder in a mortar, and extracted with boiling CH2Cl2 (20 ml). Filtration and evaporation left
a black mass which was chromatographed (SiO2, 15 30% AcOEt/hexane: 9 (0.02 g , 18%). 1H-NMR: 3.65 (s,
3 H); 6.21, 6.27, 6.75 (br., 1 H each); 7.30 (dm, J 7.8, 1 H); 7.68 (dm, J 7.8, 1 H); 8.50 (d, J 3.9, 1 H); 8.66
(br., 1 H). 13C-NMR: 35.02 (q); 108.16 (d); 109.72 (d); 123.18 (d); 124.68 (d); 129.21 (s); 130.72 (s); 135.44 (d);
.
147.58 (d); 149.12 (d). EI-MS: 158 (100, M ), 157 (39), 130 (11).
REFERENCES
[1] L. Marion, in −The Alkaloids×, Eds. R. H. F. Manske and H. L. Holmes, Academic Press, New York, 1950,
Vol. 1, p. 228; L. Marion, in −The Alkaloids×, Ed. R. H. F. Manske, Academic Press, New York, 1960, Vol. 6,
p. 128; W. A. Ayer, T. E. Habgood, in −The Alkaloids×, Ed. R. H. F. Manske, Academic Press, New York,
1968, Vol. 11, p. 477; G. M. Strunz, J. A. Findlay, in −The Alkaloids×, Ed. A. Brossi, Academic Press,
Orlando, 1985, Vol. 26, p. 121.
[2] A. Pictet, A. Rotschy, Ber. Dtsch. Chem. Ges. 1904, 37, 1225.
[3] R. B. Woodward, R. Hoffmann, J. Am. Chem. Soc. 1965, 87, 395.