over potassium carbonate, filtered, and concentrated. The product
was purified by radial PLC (silica gel, 1% TEA/20% EtOAc/
hexanes) to afford 3 mg (50%) of 8 as a yellow oil: 1H NMR (300
MHz, CDCl3) δ 8.50 (d, J ) 1.8 Hz, 1H), 8.39 (d, J ) 1.8 Hz,
1H), 7.74 (s, 1H), 6.75-6.62 (m, 1H), 5.82 (dd, J ) 17.7, 0.5 Hz,
1H), 5.38 (dd, J ) 11.0, 0.5 Hz, 1H), 3.23 (dt, J ) 1.8, 8.7 Hz,
1H), 3.08 (t, J ) 8.1 Hz, 1H), 2.31 (q, J ) 8.0 Hz, 1H), 2.20 (s,
3H), 2.10-1.65 (m, 3H); HRMS calcd for C12H16N2 ([M + H]+)
189.1392, found 189.1396.
MHz, CDCl3) δ 8.60 (d, J ) 2.4 Hz, 1H), 8.49 (d, J ) 2.4 Hz,
1H), 7.80 (t, J ) 2.4 Hz, 1H), 3.25 (t, J ) 8.4 Hz, 1H), 3.20 (s,
1H), 3.09 (t, J ) 8.4 Hz, 1H), 2.36-2.26 (m, 1H), 2.26-2.15 (m,
1H), 2.17 (s, 3H), 2.02-1.90 (m, 1H), 1.88-1.76 (m, 1H), 1.75-
1.64 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 151.7, 149.2, 138.9,
138.2, 119.3, 80.8, 80.5, 68.6, 57.2, 40.6, 35.5, 22.9.
(S)-6-Chloro-5-(1-decynyl)nicotine (11): A solution of 6-chloro-
5-iodonicotine (4a) (72 mg, 0.22 mmol, 1.0 equiv), bis(triphen-
ylphosphine)palladium(II) chloride (15 mg, 0.022 mmol, 0.1 equiv),
and copper iodide (4 mg, 0.022 mmol, 0.1 equiv) in freshly distilled
triethylamine (3 mL) was degassed with argon for 20 min, then
treated dropwise with 1-decyne (45 µL, 0.24 mmol, 1.1 equiv) for
42 h. One milliliter of a saturated aqueous solution of sodium
bicarbonate was added. The mixture was extracted with methylene
chloride (2 × 5 mL). The combined organic layers were dried over
anhydrous sodium sulfate, filtered, and concentrated. The crude
product was purified using radial PLC (silica gel, 1% TEA/20%
ethyl acetate/hexanes) to afford 48 mg (66%) of 11 as a colorless
oil: [R]30D -108 (c 1.4, CH2Cl2); IR (neat) 2927, 2855, 2783, 1399,
(S)-6-Chloro-5-[(triisopropylsilyl)ethynyl]nicotine (9): A solu-
tion of 6-chloro-5-iodonicotine (4a) (47.5 mg, 0.15 mmol, 1.0
equiv), bis(triphenylphosphine)palladium(II) chloride (11 mg, 0.015
mmol, 0.1 equiv), and copper iodide (3 mg, 0.015 mmol, 0.1 equiv)
in freshly distilled triethylamine (3 mL) was degassed with argon
for 20 min, then treated dropwise with (triisopropylsilyl)acetylene
(37 µL, 0.165 mmol, 1.1 equiv). The mixture was stirred at room
temperature for 15 h. The mixture was diluted in ethyl ether and
filtered through a pad of Celite. The filtrate was washed with a
10% solution of ammonium hydroxide until the persistent blue color
disappeared. The organic layer was washed once with deionized
water, dried over sodium sulfate, filtered, and concentrated. The
crude product was purified using radial PLC (silica gel, 1% TEA/
20% EtOAc/hexanes) to afford 135 mg (99%) of 9 as a yellow oil:
1
1095 cm-1; H NMR (400 MHz, CDCl3) δ 8.17 (d, J ) 1.8 Hz,
1H), 7.74 (d, J ) 1.8 Hz, 1H), 3.21 (dt, J ) 1.8, 8.4 Hz, 1H), 3.05
(t, J ) 8.4 Hz, 1H), 2.46 (t, J ) 6.9 Hz, 2H), 2.29 (q, J ) 8.4 Hz,
1H), 2.22-2.18 (m, 2H), 2.15 (s, 3H), 2.10-1.88 (m, 1H), 1.88-
1.78 (m, 1H), 1.70-1.60 (m, 2H), 1.52-1.42 (m, 2H), 1.36-1.24
(m, 8H), 0.90-0.85 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 151.0,
147.3, 140.6, 138.0, 98.7, 94.5, 76.2, 68.0, 57.2, 40.6, 35.5, 32.1,
29.4, 29.3, 29.1, 28.6, 22.90, 22.88, 19.9, 14.4; HRMS calcd for
C20H29ClN2 ([M + H]+) 333.2098, found 333.2108.
[R]31 -109 (c 0.35, CH2Cl2); IR (neat) 2944, 2866, 2781, 1462,
D
1397, 1077, 882 cm-1; H NMR (300 MHz, CDCl3) δ 8.22 (d, J
1
) 2.4 Hz, 1H), 7.80 (d, J ) 2.4 Hz, 1H), 3.24 (dt, J ) 2.4, 8.4 Hz,
1H), 3.08 (t, J ) 8.1 Hz, 1H), 2.32 (q, J ) 9.0 Hz, 1H), 2.25 (m,
1H), 2.18 (s, 3H), 2.02-1.90 (m, 1H), 1.90-1.76 (m, 1H), 1.76-
1.62 (m, 1H), 1.15-1.13 (m, 21H); 13C NMR (75 MHz, CDCl3) δ
151.6, 148.0, 140.7, 137.9, 120.6, 101.4, 99.9, 68.1, 57.2, 40.7,
35.5, 22.9, 18.9, 11.5; HRMS calcd for C21H33ClN2Si ([M + H]+)
377.2180, found 377.2198.
(S)-5-(1-Decynyl)nicotine (12): Zinc powder (120 mg) was
added to a solution of (S)-6-chloro-5-(1-decynyl)nicotine (11) (28
mg, 0.075 mmol) in acetic acid (3 mL). The mixture was stirred at
70 °C for 10 h. The solvent was removed by evaporation, and the
residue was dissolved in methylene chloride and filtered through a
pad of Celite. The crude residue was purified by radial PLC (silica
gel, 1% TEA/20% EtOAc/hexanes) to afford 10 mg (46%) of 12
(S)- 5-[(Triisopropylsilyl)ethynyl]nicotine (10): Zinc powder
(100 mg) was added to a solution of (S)-6-chloro-5-[(triisopropyl-
silyl)ethynyl]nicotine (9) (40 mg, 0.10 mmol) in acetic acid (3 mL).
The mixture was stirred at 75 °C for 16 h. Since starting material
was present by TLC, an extra 140 mg of zinc powder was added
to the reaction mixture. The starting material spot was gone after
5 h. The mixture was poured into a saturated aqueous solution of
sodium bicarbonate and then treated with solid sodium carbonate
until a basic pH was reached. The aqueous layer was extracted
with methylene chloride. The organic layers were combined, dried
over anhydrous sodium sulfate, filtered, and concentrated. The crude
product was purified by radial PLC (silica gel, 1% TEA/20%
as a colorless oil: [R]29 -83 (c 0.5, CH2Cl2); IR (neat) 2928,
D
2856, 2780, 1454 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.49 (d, J
) 1.8 Hz, 1H), 8.39 (d, J ) 1.8 Hz, 1H), 7.70 (t, J ) 1.8 Hz, 1H),
3.23 (dt, J ) 1.8, 8.7 Hz, 1H), 3.05 (t, J ) 8.1 Hz, 1H), 2.40 (t, J
) 7.2 Hz, 2H), 2.28 (q, J ) 9.6 Hz, 1H), 2.22-2.17 (m, 1H), 2.16
(s, 3H), 2.00-1.90 (m, 1H), 1.88-1.78 (m, 1H), 1.78-1.64 (m,
1H), 1.64-1.54 (m, 2H), 1.48-1.36 (m, 2H), 1.36-1.20 (m, 8H),
0.90-0.86 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 151.3, 148.0,
138.5, 137.6, 121.2, 100.1, 94.1, 77.5, 68.8, 57.2, 40.7, 35.4, 32.1,
29.4, 29.3, 29.2, 28.8, 22.9, 19.7, 14.4; HRMS calcd for C20H30N2
([M + H]+) 299.2487, found 299.2487.
EtOAc/hexanes) to afford 19 mg (52%) of 10 as a yellow oil: [R]29
D
-130 (c 0.5, CH2Cl2); IR (neat) 2944, 2865, 1780, 2158, 1500,
1
1414, 1153, 996, 883 cm-1; H NMR (300 MHz, CDCl3) δ 8.57
(d, J ) 1.8 Hz, 1H), 7.44 (d, J ) 1.8 Hz, 1H), 7.75 (t, J ) 1.8 Hz,
1H), 3.25 (dt, J ) 1.5, 8.7 Hz, 1H), 3.07 (t, J ) 8.1 Hz, 1H), 2.31
(q, J ) 8.1 Hz, 1H), 2.24-2.14 (m, 1H), 2.17 (s, 3H), 2.04-1.68
(m, 3H), 1.15-1.11 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 151.9,
148.7, 138.5, 137.8, 120.7, 103.8, 94.6, 68.8, 57.3, 40.7, 35.4, 22.9,
18.9, 11.5; HRMS calcd for C21H34N2Si ([M + H]+) 343.2570,
found 343.2560.
Acknowledgment. NMR and mass spectra were obtained
at NCSU instrumentation laboratories, which were established
by grants from the North Carolina Biotechnology Center and
the National Science Foundation (Grants CHE-0078253 and
CHE-9509532). F.F.W. thanks GlaxoSmithKline for the Bur-
roughs-Wellcome Research Fellowship for a second year
graduate student, and Eli Lilly for the Eli Lilly Research
Fellowship for a third year graduate student.
(S)-SIB-1508Y1,3 (1): A solution of (S)-5-[(triisopropylsilyl)-
ethynyl]nicotine (10) (32 mg, 0.093 mmol, 1.0 equiv) in THF (2
mL) was treated at room temperature with a 1.0 M solution of
TBAF (112 µL, 0.112 mmol, 1.2 equiv). The mixture was stirred
at room temperature for 20 min. The solvent was then removed
under pressure and the crude residue purified by radial PLC (silica
gel, 1% TEA/50% EtOAc/hexanes) to afford 17 mg (98%) of SIB-
1508Y as a brown oil: [R]30D -162 (c 0.77, EtOH); 1H NMR (400
Supporting Information Available: General experimental
methods and NMR spectra for 6-11, 1, and 12. This material is
JO0616052
J. Org. Chem, Vol. 71, No. 22, 2006 8675