C. Lenz et al. / Bioorg. Med. Chem. 13 (2005) 4434–4442
4439
2959, 2812, 1730, 1670, 1423, 1270, 1210, 835 cmꢀ1; H
NMR d 0.87 (t, J = 7.4 Hz, 6H, 2 · NCH2CH2CH3),
1.38–1.50 (m, 4H, 2 · NCH2CH2CH3), 1.65 (dddd,
J = 12.5, 12.1, 10.4, 5.5 Hz, 1H, 4-Hax), 1.92–1.96 (m,
1H, 4-Heq), 2.35 (ddd, J = 17.3, 10.4, 4.2 Hz, 1H, 3-
Hax), 2.38–2.44 (m, 4H, 2 ·NCH2CH2CH3), 2.47–2.56
(m, 2H, 6-H2), 2.62 (ddd, J = 17.3, 5.5, 3.6 Hz, 1H, 3-
Heq), 2.83 (dddd, J = 12.1, 10.3, 4.9, 2.9 Hz, 1H, 5-
C16H25NO2: C, 72.97; H, 9.57; N, 5.32. Found: C,
72.64; H, 9.87; N, 5.25.
1
3.5. Methyl 2-(3-hydroxyprop-1-yn-1-yl)-5-(dipropyla-
mino)-cyclohex-1-ene-1-carboxylate (6c)
To a suspension of Pd(PPh3)4 (17 mg, 0.015 mmol) and
CuI (3.7 mg, 0.019 mmol) in THF (3.5 mL) were added
a solution of 3 (38 mg, 0.1 mmol) in THF (0.5 mL),
propargyl alcohol (40 lL, 0.68 mmol) and piperidine
(75 lL, 0.58 mmol). After being stirred at room temper-
ature for 30 min, saturated aqueous NaHCO3 was
added and the aqueous layer was extracted with EtOAc.
The combined organic layers were dried (MgSO4) and
evaporated. The residue was purified by flash chromat-
ography (CH2Cl2–MeOH 95:5) to give 6c as a yellowish
oil (22 mg, 77%): IR (film) 3425, 2958, 2869, 2210, 1704,
Hax), 3.81 (s, 3H, CO2Me); 13C NMR
d 11.7
(NCH2CH2CH3), 22.1 (NCH2CH2CH3), 25.0, 27.7,
28.9 (C-3, C-4, C-6), 52.2 (CO2CH3), 52.5
(NCH2CH2CH3), 54.6 (C-5), 118.3 (q, CF3), 122.2 (C-
1), 151.0 (C-2), 164.9 (CO2CH3); EIMS 387 (M+); Anal.
Calcd for C15H24F3NO5S: C, 46.50; H, 6.24; N, 3.62.
Found: C, 46.80; H, 6.37; N, 3.61.
3.3. Methyl 2-(trimethylsilylethynyl)-5-(dipropylamino)-
cyclohex-1-ene-1-carboxylate (6a)
1
1612, 1435, 1249, 1030, 764 cmꢀ1; H NMR d 0.87 (t,
J = 7.3 Hz, 6H, 2 · NCH2CH2CH3), 1.40–1.50 (m, 5H,
2 · NCH2CH2CH3, 4-H), 1.70–1.90 (m, 2H, 4-H,
CH2OH), 2.20–2.28 (m, 1H, 3-Hax), 2.32–2.52 (m, 6H,
2 · NCH2CH2CH3, 3-H and/or 6-H), 2.56–2.61 (m,
1H, 3-H or 6-H), 2.78 (m, 1H, 5-H), 3.77 (s, 3H,
CO2Me), 4.46 (s, 2H, CH2OH); 13C NMR 11.8
(NCH2CH2CH3), 21.9 (NCH2CH2CH3), 24.7, 29.7,
32.9 (C-3, C-4, C-6), 51.7, 51.8, 52.5 (CH2OH, CO2CH3,
NCH2CH2CH3), 55.6 (C-5), 85.4, 95.3 (C„C), 128.2,
128.6 (C-1, C-2), 167 (CO2CH3); EIMS 293 (M+); HRE-
IMS calcd for C17H27NO3: 293.1991; Found: 293.1993
(M+).
To a suspension of PdCl2(PPh3)2 (43 mg, 0.06 mmol)
and CuI (17 mg, 0.09 mmol) in THF (15 mL) were
added 3 (295 mg, 0.76 mmol), trimethylsilylacetylene
(428 lL, 3.0 mmol), and piperidine (449 lL, 4.5 mmol).
After being stirred at room temperature for 30 min, sat-
urated aqueous NaHCO3 was added and the aqueous
layer was extracted with EtOAc. The combined organic
layers were dried (MgSO4) and evaporated. The residue
was purified by flash chromatography (CH2Cl2–MeOH
97:3) to give 6a as a slightly yellowish oil (224 mg,
88%): IR (film) 2958, 2807, 2144, 1708, 1608, 1250,
1
844 cmꢀ1; H NMR d 0.20 (s, 9H, Si(CH3)3), 0.85 (t,
J = 7.3 Hz, 6H, 2 · NCH2CH2CH3), 1.36–1.46 (m,
5H, 2 · NCH2CH2CH3, 4-Hax), 1.83 (dddd, J = 12.6,
5.0, 4.6, 2.6 Hz, 1H, 4-Heq), 2.21 (dddd, J = 18.3, 10.8,
4.6, 2.3 Hz, 1H, 3-Hax), 2.36–2.43 (m, 5H,
2 · NCH2CH2CH3, 6-Hax), 2.44–2.52 (m, 1H, 6-Heq),
2.57 (dddd, J = 18.3, 5.0, 1.9, 1.9 Hz, 1H, 3-Heq), 2.75
(dddd, J = 12.0, 10.7, 4.9, 2.6 Hz, 1H, 5-Hax), 3.78 (s,
3H, CO2CH3); EIMS 355 (M+); Anal. Calcd for
C19H33NO2Si: C, 68.01; H, 9.91; N, 4.17. Found: C,
67.99; H, 9.66; N, 4.14.
3.6. Methyl 2-cyano-5-(dipropylamino)cyclohex-1-ene-1-
carboxylate (6d)
To a solution of 3 (34 mg, 0.09 mmol) in benzene (4 mL)
were added potassium cyanide (23 mg, 0.35 mmol), 18-
crown-6 (46 mg, 0.17 mmol), and Pd(PPh3)4 (10 mg,
0.009 mmol). After being refluxed for 1.5 h, the mixture
was cooled to room temperature, saturated aqueous
NaHCO3 was added, and the aqueous layer was ex-
tracted with EtOAc. The combined organic layers were
dried (MgSO4) and evaporated. The residue was purified
by flash chromatography (petroleum ether–EtOAc 7:3)
to give 6d as a yellowish oil (14 mg, 61%): IR (film)
3.4. Methyl 2-ethynyl-5-(dipropylamino)-cyclohex-1-ene-
1-carboxylate (6b)
2958, 2811, 2217, 1727, 1631, 1249 cmꢀ1 1H NMR
;
To a solution of 6a (28 mg, 0.08 mmol) in THF (3 mL)
was added Bu4NF (100 lL, 1 M solution in THF) at
ꢀ20 ꢁC. After being stirred at this temperature for
40 min, saturated aqueous NaHCO3 was added, and
the aqueous layer was extracted with EtOAc. The com-
bined organic layers were dried (MgSO4) and evapo-
rated. The residue was purified by flash
chromatography (petroleum ether–EtOAc 6:4) to give
6b as a slightly yellowish oil (19 mg, 86%): IR (film)
0.87 (t, J = 7.4 Hz, 6H, 2 · NCH2CH2CH3), 1.39–1.45
(m, 4H, 2 · NCH2CH2CH3), 1.49 (dddd, J = 12.7,
11.7, 10.5, 5.4 Hz, 1H, 4-Hax), 1.93 (dddd, J = 12.7,
5.2, 4.7, 2.5 Hz, 1H, 4-Heq), 2.30 (dddd, J = 19.2, 10.5,
4.7, 2.5 Hz, 1H, 3-Hax), 2.38–2.46 (m, 4H,
2 · NCH2CH2CH3), 2.42–2.54 (m, 1H, 3-Heq or 6-H),
2.58–2.70 (m, 2H, 3-Heq or 6-H), 2.79 (dddd, J = 11.7,
10.4, 5.2, 2.9 Hz, 1H, 5-Hax), 3.85 (s, 3H, CO2CH3);
EIMS 264 (M+); HREIMS calcd for C15H24N2O2:
264.1838; Found: 264.1841 (M+).
3288, 2958, 2809, 2090, 1725, 1614, 1238, 765 cmꢀ1
;
1H NMR d 0.87 (t, J = 7.4 Hz, 6H, 2 · NCH2CH2CH3),
1.36–1.52 (m, 5H, 2 · NCH2CH2CH3, 4-Hax), 1.85
(dddd, J = 12.6, 5.0, 4.7, 2.6 Hz, 1H, 4-Heq), 2.23 (dddd,
J = 18.3, 10.8, 4.7, 2.4 Hz, 1H, 3-Hax), 2.35–2.49 (m, 6H,
2 · NCH2CH2CH3, 6-H2), 2.57 (dddd, J = 18.3, 5.0, 2.1,
2.1 Hz, 1H, 3-Heq), 2.77 (dddd, J = 12.0, 10.7, 5.0,
2.6 Hz, 1H, 5-Hax), 3.38 (s, 1H, C„CH), 3.78 (s, 3H,
CO2Me); EIMS 263 (M+); Anal. Calcd for
3.7. 1-[2-Hydroxy-5-(dipropylamino)-cyclohex-1-en-1-yl]-
ethanone (4)
A mixture of 1 (425 mg, 2.2 mmol) and Ac2O (1.428 mL,
15.1 mmol) was added to BF3Æ2CH3COOH (4.161 mL,
10.8 mmol, 36%) at 0 ꢁC. After being stirred at this tem-
perature for 30 min and at room temperature for 16 h, a