5872
R.-L. Li et al. / Tetrahedron 69 (2013) 5867e5873
128.21, 128.16, 128.04, 127.88, 126.12, 114.31, 55.28, 50.40, 42.70,
36.42, 28.83.32
160.93, 147.24, 144.79, 133.32, 130.82, 130.74, 128.47, 128.42, 128.14,
126.45, 126.41, 126.04, 115.31, 115.10, 61.89, 61.71, 61.37, 53.52,
48.22, 45.89. 19F NMR (376 MHz, CDCl3)
d¼ꢂ115.03. HRMS-ESI (m/
4.3. One-pot procedure for the synthesis of3-Chloropiperidines
z): [MþH]þ calcd for C24H23ClFN, 380.1576; found: 380.1573.
The reaction was carried out in open air system. To a 100 mL
flask were added 1 mmol alkenylamine, 50 mol % CuCl2$2H2O, and
20 mL of toluene. The reaction mixture was refluxed for 24 h. After
cooling to room temperature, the reaction mixture was washed
with water (25 mLꢁ3), dried over MgSO4, and was concentrated to
give an oil. Flash column chromatography (petroleum ether/ethyl
acetate¼100:1) gave the corresponding products.
4.4.5. N-(4-Isopropylbenzyl)-5-chloro-3,3-diphenylpiperidine
(2e). White solid. Mp 98e99 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.43e6.96 (m, 14H), 3.89 (tt, J¼11.8, 4.0 Hz, 1H), 3.74e3.52 (m,
3H), 3.26 (dd, J¼10.3, 4.2 Hz, 1H), 3.09e2.88 (m, 2H), 2.43e2.32 (m,
2H), 2.23 (t, J¼10.6 Hz, 1H), 1.31 (dd, J¼6.9, 0.6 Hz, 6H). 13C NMR
(100 MHz, CDCl3)
d¼148.07, 147.39, 144.96, 134.91, 129.22, 128.61,
128.35, 128.05, 126.44, 126.36, 125.93, 62.20, 62.08, 61.24, 53.70,
48.29, 46.02, 33.84, 24.08. HRMS-ESI (m/z): [MþH]þ calcd for
C27H30ClN, 404.2140; found: 404.2140.
4.4. One-pot two-step preparation of 3-chloropiperidines
The reaction was carried out in open air system. To a 100 mL
flask were added 1 mmol alkenylamine, 100 mol % CuCl2$2H2O,
and 20 mL of THF. The reaction mixture was stirred at room
temperature for 3 h, and then refluxed for 18 h. After cooling to
room temperature, the reaction mixture was washed with water
(25 mLꢁ3), dried over MgSO4, and was concentrated to give an
oil. Flash column chromatography (petroleum ether/ethyl
acetate¼100:1) gave the corresponding products.
4.4.6. 1-(4-Bromobenzyl)-5-chloro-3,3-diphenylpiperidine (2f). 1H
NMR (400 MHz, CDCl3)
d
¼7.56 (d, J¼7.7 Hz, 2H), 7.40e7.16 (m, 12H),
3.97 (tt, J¼11.6, 3.9 Hz, 1H), 3.68e3.58 (m, 3H), 3.28 (dd, J¼10.2,
4.1 Hz, 1H), 3.12 (d, J¼12.6 Hz, 1H), 2.48e2.37 (m, 2H), 2.31 (t,
J¼10.5 Hz, 1H). 13C NMR (100 MHz, CDCl3)
¼146.05, 143.61, 135.54,
d
130.38, 129.79, 127.31, 127.04, 125.35, 125.28, 124.95, 120.18, 60.84,
60.67, 60.25, 52.30, 47.10, 44.72. HRMS-ESI (m/z): [MþH]þ calcd for
C24H23BrClN, 440.0775; found: 440.0776.
4.4.1. N-Benzyl-5-chloro-3,3-diphenylpiperidine (2a). Oil. 1H NMR
4.4.7. N-(4-Nitrobenzyl)-2-(chloromethyl)-4,4-diphenylpyrrolidine
(400 MHz, CDCl3)
d
¼7.44e7.17 (m, 15H), 3.94 (ddd, J¼14.9, 8.1,
(2g). 1H NMR (400 MHz, CDCl3)
d
¼8.33e7.27 (m, 14H), 4.27 (d,
3.9 Hz, 1H), 3.73e3.64 (m, 3H), 3.30 (dd, J¼10.2, 3.8 Hz, 1H), 3.08 (d,
J¼14.2 Hz, 1H), 3.93 (d, J¼9.6 Hz, 1H), 3.81 (d, J¼14.2 Hz, 1H),
J¼12.5 Hz, 1H), 2.40 (dd, J¼26.3, 12.4 Hz, 2H), 2.29 (t, J¼10.6 Hz,1H).
3.48e3.41 (m, 2H), 3.26 (d, J¼8.8 Hz, 1H), 3.12e3.08 (m, 2H), 2.77
13C NMR (100 MHz, CDCl3)
d
¼146.23, 143.79, 136.50, 128.21, 127.47,
(d, J¼12.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
¼128.61, 127.93,
d
127.28, 127.00, 126.36, 125.33, 125.30, 124.88, 61.44, 60.90, 60.29,
52.53, 47.14, 44.85. HRMS-ESI (m/z): [MþH]þ calcd for C24H24ClN,
362.1670; found: 362.1669.
127.40, 127.24, 127.21, 127.18, 125.80, 125.60, 125.25, 125.04, 122.68,
122.60, 64.08, 63.30, 57.95, 52.08, 46.17, 41.10. HRMS-ESI (m/z):
[MþH] calcd for C24H23ClN2O2: 407.1521; found: 407.1525.
4.4.2. N-(4-Methylbenzyl)-5-chloro-3,3-diphenylpiperidine
4.4.8. 5-Chloro-1-isobutyl-3,3-diphenylpiperidine (2h). 1H NMR
(2b). White solid. Mp 135e136 ꢀC. 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d
¼7.35e7.31 (m, 2H), 7.17 (dd, J¼15.1, 7.1 Hz, 4H),
d
¼7.42e7.01 (m, 14H), 3.89 (ddd, J¼15.1, 8.1, 3.9 Hz, 1H), 3.65e3.54
(m, 3H), 3.32e3.22 (m, 1H), 3.03 (d, J¼12.3 Hz, 1H), 2.40 (s, 3H),
2.38e2.19 (m, 3H). 13C NMR (100 MHz, CDCl3)
7.11e7.03 (m, 4H), 3.75 (tt, J¼10.9, 3.9 Hz, 1H), 3.47 (d, J¼12.1 Hz,
1H), 3.15 (dd, J¼10.1, 3.7 Hz, 1H), 2.89e2.83 (m, 1H), 2.24 (dd,
J¼24.7, 12.6 Hz, 1H), 2.15 (d, J¼12.2 Hz, 1H), 2.10 (d, J¼7.2 Hz, 2H),
2.02 (t, J¼10.5 Hz,1H), 1.79 (td, J¼13.4, 6.7 Hz,1H), 0.86 (d, J¼3.4 Hz,
d
¼146.31, 143.88,
135.96, 133.38, 128.19, 127.95, 127.54, 127.29, 126.99, 125.37, 125.30,
124.86, 61.18, 60.84, 60.29, 52.62, 47.16, 44.91, 20.14. HRMS-ESI (m/
z): [MþH]þ calcd for C25H26ClN, 376.1827; found: 376.1826.
Crystal data for compound 2b: C24H24NCl, M¼375.92, mono-
3H), 0.85 (d, J¼3.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼146.51,
d
144.24, 127.67, 127.28, 126.90, 125.40, 125.28, 124.81, 65.62, 62.56,
60.53, 52.81, 47.27, 45.11, 24.58, 20.10, 19.81. HRMS-ESI (m/z):
[MþH]þ calcd for C21H26ClN, 328.1827; found: 328.1828.
clinic, a¼11.830(4) A, b¼10.224(4) A, c¼16.394(6) A,
a
¼90.00ꢀ,
ꢀ
ꢀ
ꢀ
3
ꢀ
ꢀ
b
¼92.623(5)ꢀ,
¼90.00 , V¼1980.8(13) A , T¼113(2) K, space group
g
P2(1)/c, Z¼4,
m
(Mo K
a
)¼0.202 mmꢂ1, 22,442 reflections measured,
4.4.9. N-Benzyl-3-chloro-5,5-dimethylpiperidine
(400 MHz, CDCl3)
(2i). 1H
NMR
4806 independent reflections (Rint¼0.0496). The final R1 value was
d
¼7.34e7.11 (m, 5H), 4.03 (ddt, J¼11.8, 10.8,
0.0400 (I>2
s
(I)). The final wR(F2) value was 0.0961 (I>2
s
(I)). The
4.5 Hz, 1H), 3.47 (d, J¼13.4 Hz, 1H), 3.38 (d, J¼13.4 Hz, 1H),
3.16e2.92 (m, 1H), 2.31 (d, J¼11.0 Hz, 1H), 1.92 (t, J¼10.7 Hz, 1H),
1.67 (d, J¼11.1 Hz, 1H), 1.33e1.17 (m, 2H), 0.98 (s, 3H), 0.80 (s, 3H).
final R1 value was 0.0523 (all data). The final wR(F2) value was
0.1023 (all data).34
13C NMR (100 MHz, CDCl3)
d
¼138.53, 128.68, 128.28, 127.06, 64.52,
4.4.3. N-(4-Methoxybenzyl)-5-chloro-3,3-diphenylpiperidine
62.33, 61.93, 54.26, 48.41, 33.41, 29.32, 25.12. HRMS-ESI (m/z):
(2c). White solid. Mp 99e100 ꢀC. 1H NMR (400 MHz, CDCl3)
[MþH]þ calcd for C14H20ClN: 238.1357; found: 238.1360.
d
¼7.14e7.22 (m, 12H), 7.02 (d, J¼7.7 Hz, 1H), 6.81 (d, J¼8.5 Hz, 1H),
3.78 (d, J¼13.4 Hz, 1H), 3.75 (s, 3H), 3.51e3.47 (m, 3H), 3.14 (d,
J¼8.5 Hz, 1H), 2.92 (d, J¼12.6 Hz, 1H), 2.26 (t, J¼12.2 Hz, 1H), 2.13
4.4.10. 2-Benzyl-4-chloro-2-azaspiro[5.5]undecane (2j). 1H NMR
(400 MHz, CDCl3)
d
¼7.32e7.28 (m, 5H), 4.15 (t, J¼11.3 Hz, 1H), 3.59
(dd, J¼25.8, 11.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d¼157.72,
(d, J¼13.3 Hz,1H), 3.46 (d, J¼13.3 Hz,1H), 3.19 (d, J¼7.3 Hz,1H), 2.71
(d, J¼11.4 Hz, 1H), 2.19 (d, J¼11.6 Hz,1H), 2.07 (t, J¼10.5 Hz, 1H), 1.65
(d, J¼11.2 Hz, 2H), 1.47e1.11 (m, 8H), 0.99e0.77 (m, 2H). 13C NMR
146.34, 143.89, 129.42, 128.57, 127.52, 127.31, 127.01, 125.42, 125.31,
124.88, 112.66, 60.85, 60.75, 60.36, 54.26, 52.64, 47.19, 44.96.
HRMS-ESI (m/z): [MþH]þ calcd for C25H26ClNO, 392.1776; found:
392.1768.
(100 MHz, CDCl3)
d
¼138.68, 128.64, 128.26, 127.06, 62.63, 62.41,
62.06, 54.05, 38.37, 36.09, 32.94, 29.77, 26.64, 21.60, 21.56. HRMS-
ESI (m/z): [MþH]þ calcd for C17H24ClN: 278.1670; found: 278.1672.
4.4.4. N-(4-Fluorobenzyl)-5-chloro-3,3-diphenylpiperidine
(2d). White solid. Mp 109e110 ꢀC. 1H NMR (400 MHz, CDCl3)
4.4.11. N-Isopropyl-5-chloro-3,3-diphenylpiperidine (2k). Oil. 1H
d
¼7.24e6.90 (m, 14H), 3.78 (tt, J¼11.8, 4.0 Hz, 1H), 3.54e3.44 (m,
NMR (400 MHz, CDCl3)
d
¼7.51e7.14 (m, 10H), 3.94e3.83 (m, 1H),
3H), 3.11 (dd, J¼10.3, 4.3 Hz, 1H), 2.95e2.90 (m, 1H), 2.29e2.18 (m,
3.59 (d, J¼12.1 Hz, 1H), 3.22 (d, J¼6.3 Hz, 1H), 3.08e2.97 (m, 2H),
2H), 2.12 (t, J¼10.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
¼163.50,
d
2.53e2.29 (m, 3H), 1.15 (d, J¼6.6 Hz, 3H), 1.12 (d, J¼6.6 Hz, 3H). 13C