A. Pianaro et al. / Tetrahedron: Asymmetry 23 (2012) 635–642
641
strong bands), 1098, 956, 836–812, 667. MS (70 eV), m/z (%): 368
4.8. Synthesis of 2-methyl-6-alkylpiperidines
(M+, 0.1), 196 (25), 173 (base peak, 100), 172 (37), 168 (10), 155
(23), 139 (5), 125 (10), 111 (20), 97 (33), 91 (48), 83 (32), 69
(28), 55 (28), 43 (24), 41 (20).12
2-Methyl-6-alkylpyridines 3–5 (59.8 mg undecyl, 91.1 mg
tridecyl, and 152.6 mg pentadecyl) were solubilized in 8 mL of
distilled methanol and 40 mL of glacial acetic acid. Next
110 mg of Pt/C 10% was added. The hydrogenation reaction
was kept at a pressure of 70 psi of H2 (g) with stirring for
72 h. The reaction mixture was filtered through a sintered glass
Buchner funnel with Celite 545 (2 g) eluting with 50 mL of dis-
tilled methanol. The solvent was evaporated in vacuo and the
product was analyzed by TLC and GC–MS.14 2-Methyl-6-alkyl-
pyridines were purified by silica gel (10 g) column chromatogra-
phy, eluting with distilled dichloromethane/ethyl acetate (9:1),
dichloromethane/ethyl acetate (1:1), ethyl acetate, and methanol.
4.7. Synthesis of 2-methyl-6-alkylpyridines
Treated 2,6-lutidine 1 (344 mg, 3.21 mmol) was solubilized in
10 mL of dry tetrahydrofuran (THF) under an argon atmosphere
with magnetic stirring and ice bath (0 °C). A hexane solution of
n-butyl-lithium (10 mol/L, 0.32 mL, 3.21 mmol) was added slowly
and, after 15 min at room temperature with magnetic stirring, the
reaction mixture was heated at reflux (35–40 °C) for 15 min for
the formation of carbanion intermediate 2. Subsequently, the cor-
responding tosylated alcohol (1000 mg, 3.21 mmol) was added
slowly over 10 min. The reaction was monitored by TLC and
stopped after 2.5 h with small ice chunks, maintaining the mag-
netic stirring and ice bath (0 °C). The reaction product was ex-
tracted with the addition of distilled water (10 mL) and distilled
ethyl acetate (3 ꢄ 100 mL). The organic phase was dried over
anhydrous Na2SO4 and the solvent was evaporated in vacuo.13
2-Methyl-6-alkylpyridine was purified by silica gel (60 g) column
chromatography with the following eluents: distilled dichloro-
methane and distilled dichloromethane/ethyl acetate (95:5). 2-
Methyl-6-undecylpyridine 3 (153.7 mg, 19% purified yield): 1H
NMR (499.88 MHz, CDCl3, TMS): d 0.88 (t, J = 6.82 Hz, 3H), 1.29
(m, 16H), 1.68 (quin, J = 8.00, 7.60 Hz, 2H), 2.53 (s, 3H), 2.74 (t,
J = 7.92 Hz, 2H), 6.94 (dd, J = 4.50, 4.40 Hz, 1H), 7.43 (d,
J = 8.00 Hz, 1H), 7.46 (t, J = 7.65 Hz, 1H). 13C NMR (62.89 MHz,
CDCl3, TMS): d 14.08 (CH3), 22.66 (CH2), 24.51 (CH3), 29.32
(CH2), 29.47 (CH2), 29.50 (CH2), 29.55 (CH2), 29.60 (CH2), 29.62
(CH2), 30.22 (CH2), 31.89 (CH2), 38.59 (CH2), 119.40 (CH),
( )-Cis
and
( )-trans-2-methyl-6-undecylpiperidines
6A–D
(97.3 mg, 99% purified yield): 1H NMR (499.87 MHz, CDCl3,
TMS): d 0.88 (t, J = 6.90 Hz, 3H), 1.25–1.80 (m, 29H), 1.95 (s,
1H), 2.69 (m, 1H), 2.86 (m, 1H). 13C NMR (125.69 MHz, CDCl3,
TMS): d 14.12 (CH3), 21.00 (CH3), 22.70 (CH2), 23.91 (CH2),
25.78 (CH2), 29.36 (CH2), 29.60 (CH2), 29.65 (CH2), 29.68 (CH2),
31.93 (CH2), 32.38 (CH2), 35.13 (CH2), 52.95 (CH), 57.27 (CH).
IR
(m
max/cmꢁ1): 3310, 2917, 2851, 1648–1581, 1412–1339,
1088–1051, 650–621. MS (70 eV), m/z (%): 253 (M+, 1), 252 (3),
238 (6), 224 (1), 210 (1), 154 (1), 126 (1), 111 (1), 98 (base peak,
100), 81 (1), 70 (2), 55 (3), 41 (3).7a,c ( )-Cis and ( )-trans-2-
methyl-6-tridecylpiperidines 7A–D (83.3 mg, 89% purified yield):
1H NMR (250.13 MHz, CDCl3, TMS): d 0.88 (t, J = 6.49 Hz, 3H),
1.25–1.80 (m, 33H), 1.95 (s, 1H), 2.69 (m, 1H), 2.87 (m, 1H).
13C NMR (62.89 MHz, CDCl3, TMS): d 14.10 (CH3), 20.67 (CH3),
22.68 (CH2), 23.76 (CH2), 25.73 (CH2), 29.25 (CH2), 29.35 (CH2),
29.58 (CH2), 29.65 (CH2), 29.67 (CH2), 31.91 (CH2), 32.03 (CH2),
34.75 (CH2), 52.97 (CH), 57.23 (CH). IR
(m
max/cmꢁ1): 3307,
2912, 2846, 1561, 1403, 1084–1045, 641. MS (70 eV), m/z (%):
281 (M+, 2), 280 (4), 266 (7), 252 (1), 238 (1), 224 (0.1), 154
(1), 126 (1), 111 (1), 98 (base peak, 100), 83 (1), 69 (2), 55 (3),
43 (3). ( )-Cis and ( )-trans-2-methyl-6-pentadecylpiperidines
8A–D (102.7 mg, 65% purified yield): 1H NMR (250.13 MHz,
CDCl3, TMS): d 0.88 (t, J = 6.48 Hz, 3H), 1.25–1.80 (m, 37H),
1.96 (s, 1H), 2.68 (m, 1H), 2.84 (m, 1H). 13C NMR (62.89 MHz,
CDCl3, TMS): d 14.10 (CH3), 20.91 (CH3), 22.68 (CH2), 23.87
(CH2), 25.75 (CH2), 29.35 (CH2), 29.58 (CH2), 29.69 (CH2), 31.92
(CH2), 32.28 (CH2), 35.01 (CH2), 52.93 (CH), 57.23 (CH). IR
120.28 (CH), 136.40 (CH), 157.61(C), 161.94 (C). IR (m
max/cmꢁ1):
2917–2851, 1590, 1575, 1454, 1302, 1140, 1083, 814–674. MS
(70 eV), m/z (%): 247 (M+, 2), 232 (0.1), 218 (1), 204 (2), 190
(2), 176 (2), 162 (3), 148 (3), 134 (11), 120 (19), 107 (base peak,
100), 93 (2), 79 (2), 65 (2), 53 (1), 41 (5). 2-Methyl-6-tridecylpyri-
dine 4 (191.0 mg, 24% purified yield): 1H NMR (400.13 MHz,
CDCl3, TMS): d 0.88 (t, J = 7.00 Hz, 3H), 1.25 (m, 20H), 1.69 (quin,
J = 8.00, 7.60 Hz, 2H), 2.53 (s, 3H), 2.74 (t, J = 7.90 Hz, 2H), 6.94
(dd, J = 3.44, 3.36 Hz, 1H), 7.43 (d, J = 8.80 Hz, 1H), 7.46 (t,
J = 7.66 Hz, 1H). 13C NMR (100.61 MHz, CDCl3, TMS): d 14.07
(CH3), 22.65 (CH2), 24.49 (CH3), 29.31 (CH2), 29.41 (CH2), 29.46
(CH2), 29.49 (CH2), 29.54 (CH2), 29.57 (CH2), 29.61 (CH2), 29.62
(CH2), 29.65 (CH2), 30.21 (CH2), 31.88 (CH2), 38.57 (CH2), 119.38
(m
max/cmꢁ1): 3304, 2915, 2846, 1645–1566, 1409–1341, 1085–
1046, 653–618. MS (70 eV), m/z (%): 309 (M+, 2), 308 (4), 294
(6), 280 (0.1), 266 (1), 154 (1), 111 (3), 98 (base peak, 100), 84
(1), 70 (2), 55 (3), 41 (3).
(CH), 120.26 (CH), 136.38 (CH), 157.59 (C), 161.93 (C). IR (mmax
/
cmꢁ1): 2917–2851, 1590, 1575, 1466, 1453, 1304, 1140, 1084,
814–674. MS (70 eV), m/z (%): 275 (M+, 6), 260 (1), 246 (2), 232
(3), 218 (2), 204 (2), 190 (3), 176 (4), 162 (5), 148 (4), 134 (16),
120 (25), 107 (base peak, 100), 93 (2), 79 (1), 65 (1), 55 (1), 41
4.9. Trifluoroacetylation of alkaloids
The alkaloids were solubilized with dry ethyl ether (1 mL) and
pyridine (0.8 mL). Next, trifluoroacetic anhydride (0.8 mL) and tri-
fluoroacetic acid (0.1 mL) were added slowly with magnetic stir-
ring in a glycerin bath (30 °C) for 30 min.15a The reaction was
stopped by the addition of distilled ethyl acetate (20 mL) and an
aqueous solution of saturated copper sulfate (2 ꢄ 20 mL). The or-
ganic phase was separated in a separating funnel, dried with anhy-
drous Na2SO4, concentrated in vacuo, and analyzed by GC–MS and
chiral GC. Trifluoroacetamides 9A–B: MS (70 eV), m/z (%): 349 (M+,
0.1), 334 (1), 280 (4), 194 (base peak, 100), 140 (5), 81 (7), 55 (11),
41 (4). Trifluoroacetamides 10A–B: MS (70 eV), m/z (%): 377 (M+,
0.1), 362 (1), 308 (4), 194 (base peak, 100), 140 (4), 81 (6), 55
(11), 41 (4). Trifluoroacetamides 11A–B: MS (70 eV), m/z (%): 405
(M+, 0.1), 390 (1), 336 (4),194 (base peak, 100), 140 (3), 81 (6),
55 (10), 41 (3).
(3). 2-Methyl-6-pentadecylpyridine
5 (125.5 mg, 15% purified
yield): 1H NMR (400.13 MHz, CDCl3, TMS): d 0.88 (t, J = 6.82 Hz,
3H), 1.25 (m, 24H), 1.69 (quin, J = 8.00, 7.60 Hz, 2H), 2.53 (s,
3H), 2.74 (t, J = 7.90 Hz, 2H), 6.94 (dd, J = 3.60, 3.56 Hz, 1H), 7.43
(d, J = 8.40 Hz, 1H), 7.46 (t, J = 7.44 Hz, 1H). 13C NMR
(100.61 MHz, CDCl3, TMS): d 14.08 (CH3), 22.66 (CH2), 24.51
(CH3), 29.33 (CH2), 29.42 (CH2), 29.50 (CH2), 29.54 (CH2), 29.62
(CH2), 29.66 (CH2), 30.21 (CH2), 31.89 (CH2), 38.59 (CH2), 119.38
(CH), 120.26 (CH), 136.37 (CH), 157.60 (C), 161.94 (C). IR (mmax
/
cmꢁ1): 2914–2849, 1589, 1573, 1467, 1454, 1302, 1140, 1083,
814–675. MS (70 eV), m/z (%): 303 (M+, 4), 288 (0.1), 274 (1),
260 (2), 246 (1), 232 (1), 218 (1), 204 (1), 190 (2), 176 (3), 162
(4), 148 (3), 134 (12), 120 (20), 107 (base peak, 100), 93 (1), 79
(1), 65 (1), 55 (1), 41 (3).