A mixture of N-benzyl-cis-2,6-bis(chloromethyl)piperidine (1)
and 6-chloro-2-chloromethyl-1-benzylazepane (16)
column chromatography on silica gel eluting with 50% EtOAc–
hexane. Pure 20 was thereby obtained as a colorless viscous oil
(3.8 g, 93%). δH (200 MHz: CDCl3; Me3Si) 1.33–1.71 (6 H, m,
3-H, 4-H, and 5-H), 2.10–2.19 (1 H, m, 6-H), 2.43–2.47 (1 H, m,
6-H), 2.70 (1 H, br s, OH), 2.73–2.89 (1 H, m, 2-H), 3.31 (1 H,
d, J 10, CH2OH), 3.52 (1 H, dd, J 5 and 4, CH2Ph), 3.84 (1 H,
dd, J 5 and 4, CH2Ph), 4.05 (2 H, d, J 10, CH2OH), 7.23–7.35
(m, 5 H); δC (200 MHz: CDCl3; Me3Si) 23.9 (t, 4-C), 25.6
(t, 5-C), 27.9 (t, 3-C), 45.9 (t, CH2Ph), 57.7 (d, 2-C), 65.2
(t, CH2OH), 126.7, 128.0, 128.6 (each d, 3 × Ar–CH), 138.8
(s, Ar–C). Found: C, 75.83; H, 9.59. Calc. for C13H19NO: C,
76.06; H, 9.33%.
Method 1. To a solution of 9 (850 mg, 3.0 mmol) and Et3N
(1.3 mL, 9.1 mmol) in CH2Cl2 (4 mL) at 0 ЊC was added drop-
wise a solution of TsCl (1.73 g, 9.1 mmol) in CH2Cl2 (3 mL).
The resulting solution was allowed to the room temperature
and stirred for 18 h. The resulting mixture was diluted with
CH2Cl2 (30 mL) and washed with H2O (3 × 20 mL). The com-
bined organic layers were dried (MgSO4) and filtered, and the
filtrate was concentrated in vacuo. The residue was purified via
column chromatography on silica gel eluting with 10% EtOAc–
hexane to afford 1 and 16 (310 mg, 38%) as an inseparable
mixture in a 3 : 1 ratio. 1H and 13C NMR signals corresponding
to 1 are essentially identical to that of authentic 1. Compound
16: δH (200 MHz, obtained as a mixture of 16 with 1, CDCl3;
Me3Si) 1.40–2.40 (6 H, m, 3-H, 4-H, and 5-H), 2.81–4.06 (8 H,
m, 2-H, 6-H, 7-H, CH2Cl, and CH2Ph), 7.22–7.45 (5 H, m, Ph);
δC (200 MHz: CDCl3; Me3Si) 23.0 (t, 4-C), 31.6 (t, 3-C), 40.0
(t, 5-C), 46.8 (t, CH2Cl), 55.1 (t, 7-C), 57.7 (d, 6-C), 59.2
(t, CH2Ph), 62.3 (d, 2-C), 127.19, 128.3, 128.7 (each d, 3 ×
Ar-CH), 139.4 (Ar-C).;m/z (positive ion FAB) 272 (Mϩ).
N-Benzyl-2-chloromethylpiperidine (21).8
A solution of 20 (2.8 g, 13.6 mmol) in dry benzene (30 mL) was
saturated with HCl (g) at 0 ЊC. After addition of thionyl
chloride (5 mL), the mixture was heated at 60 ЊC for 3 h. The
cooled reaction mixture was concentrated and neutralized with
5% Na2CO3 solution. The resulting mixture was extracted with
CH2Cl2 (3 × 50 mL) and the combined organic layers were dried
(MgSO4) and filtered, and the filtrate was concentrated in vacuo
to afford crude 21 (2.76 g, 91%). δH (200 MHz: CDCl3; Me3Si)
1.33–1.79 (6 H, 3-H, 4-H, and 5-H), 2.15–2.25 (1 H, m, 6-H),
2.64–2.82 (2 H, m, 2-H and 6-H), 3.40 (1 H, d, J 7, CH2Ph),
3.68 (2 H, d, J 10, CH2Cl), 4.04 (1 H, d, J 7, CH2Ph), 7.26–7.39
(5 H, m, Ph); δC (200 MHz: CDCl3; Me3Si) 22.7 (t, 4-C), 25.1 (t,
5-C), 28.9 (t, 3-C), 45.6 (t, CH2Cl), 51.1 (t, 6-C), 58.2 (t,
CH2Ph), 61.4 (d, 2-C), 126.9, 128.2, 128.9 (each d, 3 × Ar–CH),
Method 2. Dichloride 1 (100 mg, 0.37 mmol) was dissolved in
DMSO (5 mL) and the resulting solution was heated to 90 ЊC
for 4 h. The resulting mixture was poured into ice–water and
extracted with Et2O (2 × 30 mL). The combined organic layers
was washed with H2O (3 × 10 mL), dried (MgSO4), and filtered.
The filtrate was concentrated in vacuo. Both 1 and 16 were
1
139.5 (s, Ar–C). The H NMR, 13C NMR spectra of 21 as
1
thereby obtained as a mixture in quantitative yield. The H
an acidic salt are essentially identical to data reported
NMR, 13C NMR spectra of 1 and 16 obtained as a mixture are
previously.8
essentially identical to data obtained in Method 1.
X-Ray crystal structure determination of compound 6
Method 3. Dichloride 1 (100 mg, 0.38 mmol) was dissolved in
CH2Cl2 (5 mL) and the resulting solution was stirred at room
temperature for 18 h. Evaporation of solvent provided both 1
Crystals for structure and stereochemistry determination were
obtained by recrystallization of 6 from CH2Cl2–hexanes.
C29H37Cl2N3O4S2, M = 626.64, triclinic, a = 10.245(8), b =
1
and 16 as a mixture in quantitative yield. The H NMR, 13C
10.338(8), c = 15.970(12) Å, α = 79.037(13), β = 88.444(13), γ =
NMR spectra of 1 and 16 obtained as a mixture are essentially
identical to data obtained from Method 1.
3
¯
65.605(11)Њ, U = 1509.7(19) Å, T = 173(2) K, space group P1,
Z = 2, µ(Mo-Kα) = 0.393 mmϪ1, 6844 reflections collected,
independent/observed reflections 4307 (Rint = 0.0198), R1
0.0412, wR2 = 0.1096 [I > 2σ(I)].
=
A mixture of 2,6-bis(cyanomethyl)piperidine (17) and 6-cyano-2-
cyanomethyl-1-benzylazepane (18)
A mixture of 1 (150 mg, 0.55 mmol) and NaCN (81 mg, 1.65
mmol) in DMSO (2 mL) was heated to 90 ЊC for 4 h. The
resulting mixture was poured into ice–water and extracted with
Et2O (2 × 50 mL). The combined organic layers were washed
with H2O (3 × 30 mL), dried (MgSO4), and filtered. The filtrate
was concentrated in vacuo. The residue was purified via column
chromatography on basic alumina eluting with 10% EtOAc–
hexane. A fraction containing the mixture of 17 and 18 was
obtained (368 mg, 88%). The 17 : 18 ratio (1 : 1) was determined
by 1H NMR: δH (200 MHz, obtained as a mixture of 17 with 18,
CDCl3; Me3Si) 1.10–1.73 (m, 4 H), 1.87–2.61 (m, 8 H), 2.70–
3.23 (m, 3 H), 3.80–3.96 (m, 2 H), 7.18–7.45 (10 H, m, Ph); δC
(200 MHz: CDCl3; Me3Si) 21.2 (t), 21.9 (t), 23.4 (t), 24.0 (t),
30.0 (d), 30.2 (t), 33.0 (t), 33.6 (t), 49.2 (t), 56.9 (t), 58.6 (d), 58.7
(t), 59.0 (d), 117.8 and 118.4 (2 × CN), 126.4, 126.8, 127.1,
127.6, 128.4, and 128.6 (each d, 6 × Ar–CH), 138.0, 139.4 (each
s, 2 × Ar–C); m/z (Positive ion FAB) 253 (Mϩ).
Acknowledgements
We thank the structural Mass Spectra Group (Dr L. Pannell,
NIDDK, Bethesda, MD) for obtaining the mass spectra.
Dr B. Ganguly thanks Dr P. K. Ghosh, Director, CSMCRI for
his support.
References
1 (a) P. Kulanthaivel, Y. F. Hallock, C. Boros, S. M. Hamilton,
W. P. Janzen, L. M. Ballas, C. R. Loomis, J. B. Jiang, B. Katz,
J. R. Steniner and J. Clardy, J. Am. Chem. Soc., 1993, 115, 6452;
(b) S. Ohsima, M. Yanagisawa, A. Katoh, T. Fujii, T. Sano,
S. Matsukuma, T. Furumai, M. Fujiu, W. Kimihiro, Y. Kazuteru,
M. Arisawa and T. J. Okuda, Antibiotics, 1993, 47, 639; (c) T. Morie,
S. Kato, H. Harada, N. Yoshida, I. Fujiwara and J-I. Matsumoto,
Chem. Pharm. Bull., 1995, 43, 1137; (d ) W. W. Engel, W. G. Eberlein,
G. Mihm, R. Hammer and G. Trummlitz, J. Med. Chem., 1989, 32,
1718.
2 (a) L. Gauzy, Y. L. Merrer and J-C. Depezay, Tetrahedron Lett.,
1999, 40, 6005; (b) E. Albertini, A. Barco, S. Benetti, C. De Risi,
G. P. Pollini and V. Zanirato, Synlett, 1996, 29; (c) D. Riber,
R. Hazell and T. Skrydstrup, J. Org. Chem., 2000, 65, 5382; (d )
K. C. Nicolaou, M. E. Bunnage and K. Koide, J. Am Chem. Soc.,
1994, 116, 8402; (e) J. Armbruster, F. Stelzer, P. Landenberger,
C. Wieber, D. Hunkler, M. Keller and H. Prinzbach, Tetrahedron
Lett., 2000, 41, 5483; ( f ) L. Gauzy, Y. L. Merrer, J-C. Depezay,
F. Clerc and S. Mignani, Tetrahedron Lett., 1999, 40, 6005; (g)
A. Tuch, M. Saniere, Y. Le Merrer and J. Depezay, Tetrahedron:
Asymmetry, 1996, 7, 2901.
N-Benzyl-2-hydroxymethylpiperidine (20).7
To a solution of 19 (2.3 g, 20 mmol) in ethanol (40 mL) and
water (6 mL) was added benzyl bromide (3.58 g, 20 mmol) and
potassium carbonate (8.28 g, 60 mmol). The resulting mixture
was stirred at 80 ЊC for 12 h. Solvent was removed from the
reaction mixture and the residue was dissolved in EtOAc and
washed with H2O (3 × 30 mL), dried (MgSO4), and filtered. The
filtrate was concentrated in vacuo. The residue was purified via
J. Chem. Soc., Perkin Trans. 1, 2002, 2080–2086
2085