1730 J. Am. Chem. Soc., Vol. 120, No. 8, 1998
Masuya et al.
65.83, 110.29, 143.64, 170.55. Anal. Calcd for C15H30O3SSi: C, 56.55;
H, 9.49; S, 10.06. Found: C, 56.27; H, 9.35; S, 9.81.
mixture of 1b (0.33 mmol) and an alkene (0.3 mmol) in CH2Cl2 (0.6
mL) under a nitrogen atmosphere was added a 1.0 M hexane solution
of EtAlCl2 (0.33 mL, 0.33 mmol) at -45 °C. After the mixture was
stirred at adequate temperature until disappearance of the alkene
(monitored by TLC), a saturated aqueous NaHCO3 solution was added.
The mixture was separated, and the aqueous layer was extracted with
ether. The combined organic layer was washed with brine, and dried
over MgSO4. Concentration under reduced pressure followed by
purification by flash column chromatography (silica gel 60N, spherical,
neutral) afforded the desired product.
2-(Methylthio)propionic Acid (6). An aqueous solution of sodium
2-bromopropionate was prepared from 2-bromopropionic acid (5) (15
mL, 167 mmol), NaHCO3 (14 g, 167 mmol), and 35 mL of water. To
this was slowly added a 15% aqueous solution of MeSNa (82 mL, 175
mmol) at room temperature, and the mixture was stirred for 1 h. The
reaction mixture was acidified by dropwise addition of concentrated
hydrochloric acid using Congo Red as an indicator. The solution was
extracted with ether, and the organic layer was washed with brine, and
dried over MgSO4. Concentration followed by distillation under
reduced pressure (bp 78 °C, 1.5 mmHg) afforded 6 (19.4 g, 162 mmol,
97%) as a colorless oil: IR (neat) 3100, 1710 cm-1; 1H NMR (CDCl3,
270 MHz) δ 1.47 (d, 3 H, J ) 7.6 Hz), 2.21 (s, 3 H), 3.36 (q, 1 H, J
) 7.6 Hz), 11.81 (br s, 1 H); 13C NMR (CDCl3, 67.5 MHz) δ 14.09,
16.09, 41.72, 179.33. Anal. Calcd for C4H8O2S: C, 39.98; H, 6.71;
S, 26.68. Found: C, 39.68; H, 6.54; S, 26.91.
9-(Methylthio)bicyclo[4.3.0]non-1(9)-en-8-one (11): IR (neat)
1
1700, 1600, 1450, 1200, 950 cm-1; H NMR (CDCl3, 270 MHz) δ
1.00-1.60 (m, 3 H), 1.78-2.22 (m, 5 H), 2.30 (s, 3 H), 2.56-2.66
(m, 2 H), 3.10-3.18 (m, 1 H); 13C NMR (CDCl3, 67.5 MHz) δ 15.37,
25.27, 26.56, 29.60, 34.92, 40.68, 41.44, 131.52, 182.01, 205.12. Anal.
Calcd for C10H14OS: C, 65.89; H, 7.74; S, 17.59. Found: C, 66.18;
H, 7.88; S, 17.29.
(1R*,6S*,9S*)-1-Methoxy-9-methyl-9-(methylthio)bicyclo[4.3.0]-
nonan-8-one (12): IR (neat) 1740, 1440, 1200, 1090 cm-1; 1H NMR
(CDCl3, 270 MHz) δ 1.20-1.68 (m, 10 H, involving a singlet at 1.40),
1.76-1.90 (m, 1 H), 2.24-2.42 (m, 6 H, involving a singlet at 2.26),
3.42 (s, 3 H); 13C NMR (CDCl3, 67.5 MHz) δ 12.44, 17.73, 19.98,
21.31, 23.86, 25.09, 37.24, 39.15, 50.98, 60.67, 82.78, 215.62. Anal.
Calcd for C12H20O2S: C, 63.11; H, 8.83; S, 14.04. Found: C, 63.40;
H, 9.10; S, 14.30.
Ethyl 3-(Methylthio)-2-oxobutyrate (3b). To an ice-cooled solu-
tion of diisopropylamine (20.4 mL, 144 mmol) in THF (145 mL) was
added a 1.60 M hexane solution of butyllithium (90 mL, 144 mmol).
After 10 min, acid 6 (6.4 mL, 60 mmol) and HMPA (48 mL) were
added, and the solution was stirred for 2 h. The mixture was cooled
to -23 °C, and diethyl oxalate (9.8 mL, 72 mmol) was added. After
being stirred for 2 h at 0 °C, the mixture was acidified by dropwise
addition of diluted hydrochloric acid. The mixture was separated, and
the aqueous layer was extracted with ether. The combined organic
layer was washed with a saturated aqueous NaHCO3 solution followed
by brine, and dried over MgSO4. Concentration under reduced pressure
followed by purification by flash column chromatography afforded 3b
(2R*,3S*,4R*)-3-(Benzylthio)-2,4-dimethyl-2-(methylthio)cyclo-
pentanone (17): IR (CDCl3) 1720, 1600, 1450, 1380, 1100, 1070 cm-1
;
1H NMR (CDCl3, 270 MHz) δ 1.06 (d, 3 H, J ) 6.2 Hz), 1.22 (s, 3
H), 1.72-1.84 (m, 1 H), 1.91 (s, 3 H), 2.40-2.50 (m, 2 H), 2.78-
2.90 (m, 1 H), 3.80 (d, 1 H, J ) 12.2 Hz), 3.86 (d, 1 H, J ) 12.2 Hz),
7.20-7.35 (m, 5 H); 13C NMR (CDCl3, 67.5 MHz) δ 10.49, 17.64,
18.19, 34.45, 37.96, 43.25, 58.68, 59.95, 127.29, 128.49, 129.26, 137.97,
206.93. Anal. Calcd for C15H20OS2: C, 64.24; H, 7.19; S, 22.87.
Found: C, 64.54; H, 7.34; S, 22.91.
(10.1 g, 57 mmol, 95%) as a colorless oil: IR (neat) 1740, 1720 cm-1
;
1H NMR (CDCl3, 270 MHz) δ 1.38 (t, 3 H, J ) 7.1 Hz), 1.43 (d, 3 H,
J ) 6.9 Hz), 1.85 (s, 3 H), 4.17 (q, 1 H, J ) 6.9 Hz), 4.36 (q, 2 H, J
) 7.1 Hz); 13C NMR (CDCl3, 67.5 MHz) δ 10.11, 12.43, 13.93, 41.51,
62.50, 162.29, 184.43.
Ethyl (Z)-3-(Methylthio)-2-(triisopropylsiloxy)-2-butenoate (4b).
According to the procedure for preparation of 4a, 3b (10.1 g, 57 mmol)
was treated with NaH (2.1 g, 86 mmol) and TIPSCl (14.6 mL, 68.4
mmol) to afford 4b (16.6 g, 49.8 mmol, 87%) as a colorless oil: IR
(2S*,3S*,4R*)-3-(Benzylthio)-2,3,4-trimethyl-2-(methylthio)cyclo-
pentanone (20): IR (neat) 1730, 1500, 1450, 1380, 1240, 1050, 710
1
cm-1; H NMR (CDCl3, 270 MHz) δ 1.32 (d, 3 H, J ) 7.6 Hz), 1.49
(s, 3 H), 1.55 (s, 3 H), 2.05 (s, 3 H), 2.35 (dd, 1 H, J ) 5.4, 18.4 Hz),
2.50-2.64 (m, 1 H), 2.71 (dd, 1 H, J ) 9.5, 18.4 Hz), 3.80 (d, 1 H, J
) 12.2 Hz), 3.89 (d, 1 H, J ) 12.2 Hz), 7.20-7.35 (m, 5 H); 13C
NMR (CDCl3, 67.5 MHz) δ 13.56, 17.56, 18.17, 18.54, 18.78, 34.09,
36.77, 41.64, 60.65, 127.15, 128.59, 129.03, 137.19, 210.56. Anal.
Calcd for C16H22OS2: C, 65.26; H, 7.53; S, 21.78. Found: C, 65.06;
H, 7.76; S, 21.62.
1
(neat) 1700, 1630, 1555 cm-1; H NMR (CDCl3, 270 MHz) δ 1.04-
1.16 (m, 21 H), 1.33 (t, 3 H, J ) 7.0 Hz), 2.11 (s, 3 H), 2.25 (s, 3 H),
4.25 (q, 2 H, J ) 7.0 Hz); Anal. Calcd for C16H32O3SSi: C, 57.78; H,
9.70; S, 9.64. Found: C, 57.56; H, 9.89; S, 9.84.
(Z)-1-Acetoxy-3-(methylthio)-2-(triisopropylsiloxy)-2-butene (1b).
According to the procedure for preparation of 1a, 4b (16.6 g, 49.8
mmol) was treated with diisobutylaluminum hydride followed by acetic
anhydride and 4-(dimethylamino)pyridine to afford 1b (15.6 g, 46.8
(1S*,5R*,8S*)-8-Methyl-8-(methylthio)-2-thiabicyclo[3.3.0]octan-
7-one (22): mp 70 °C; IR (neat) 1720, 1710, 1450, 1220, 1070 cm-1
;
mmol, 94%) as a colorless oil: IR (neat) 1740, 1625 cm-1; H NMR
1H NMR (CDCl3, 270 MHz) δ 1.45 (s, 3 H), 1.56 (s, 3 H), 1.82-1.96
(m, 4 H, involving a singlet at 1.94), 2.10-2.32 (m, 2 H), 2.78-3.06
(m, 4 H); 13C NMR (CDCl3, 67.5 MHz) δ 11.97, 17.41, 23.72, 30.41,
32.38, 37.64, 46.43, 62.30, 69.85, 206.34. Anal. Calcd for C10H16-
OS2: C, 55.51; H, 7.45; S, 29.64. Found: C, 55.35; H, 7.74; S, 29.40.
(2S*,3R*)-2-Methyl-2-(methylthio)-3-phenylcyclopentanone
1
(CDCl3, 270 MHz) δ 1.05-1.25 (m, 21 H), 2.03 (s, 3 H), 2.09 (s, 3
H), 2.17 (s, 3 H), 4.95 (s, 2 H); 13C NMR (CDCl3, 67.5 MHz) δ 13.36,
14.11, 15.59, 16.46, 17.88, 60.67, 127.03, 137.55, 164.72. Anal. Calcd
for C16H32O3SSi: C, 57.78; H, 9.70; S, 9.64. Found: C, 57.51; H,
9.81; S, 9.42.
1
(24): mp 70 °C; IR (CH2Cl2) 1710, 1600, 1360, 1220, 710 cm-1; H
General Procedure for the [3+2] Cycloaddition Reaction of 1a
with Enol Ethers, Vinyl Sulfides, or Styrenes (Method A). To a
mixture of 1a (0.33 mmol) and an alkene (0.3 mmol) in CH2Cl2 (0.6
mL) was added a 1.0 M hexane solution of EtAlCl2 (0.33 mL, 0.33
mmol) at -45 °C. After the mixture was stirred at adequate temperature
until disappearance of the alkene (monitored by TLC), a saturated
aqueous NaHCO3 solution was added. The mixture was separated, and
the aqueous layer was extracted with ether. The combined organic
layer was washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The crude product was treated with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) (0.13 mL, 0.9 mmol) in benzene (1.3 mL)
for 1 day at room temperature. The mixture was poured into a saturated
aqueous NH4Cl solution. The mixture was separated, and the aqueous
layer was extracted with ether. The combined organic layer was washed
with brine, and dried over MgSO4. Concentration under reduced
pressure followed by purification by flash column chromatography
(silica gel 60N, spherical, neutral) afforded the desired product.
General Procedure for the [3+2] Cycloaddition Reaction of 1b
with Enol Ethers, Vinyl Sulfides, or Styrenes (Method B). To a
NMR (CDCl3, 270 MHz) δ 1.38 (s, 3 H), 1.84 (s, 3 H), 2.47-2.60 (m,
2 H), 2.78-2.89 (m, 1 H); 13C NMR (CDCl3, 67.5 MHz) δ 10.02,
18.04, 22.96, 35.04, 53.89, 55.96, 127.53, 128.03, 128.96, 136.91,
209.11. Anal. Calcd for C13H16OS: C, 70.87; H, 7.32; S, 14.55.
Found: C, 70.81; H, 7.62; S, 14.29.
(2R*,3S*)-3-Methyl-2-(methylthio)-3-phenylcyclopentanone (25).
This compound contains 16% of the minor diastereomer: IR (neat)
1
1730, 1380, 1260, 1150, 1070, 760, 700 cm-1; H NMR (CDCl3, 270
MHz) δ 1.36 (s, 3 H), 2.02 (s, 3 H), 2.10-2.82 (m, 4 H), 3.16 (s, 1 H),
7.20-7.40 (m, 5 H) with peaks due to the minor isomer at 1.44 (s),
2.16 (s), and 3.42 (s); 13C NMR (CDCl3, 67.5 MHz) δ 14.34, 30.17,
30.23, 33.14, 47.46, 60.36, 125.71, 126.65, 128.28, 144.58, 209.45.
Anal. Calcd for C13H16OS: C, 70.87; H, 7.32; S, 14.55. Found: C,
70.60; H, 7.49; S, 14.37.
General Procedure for the [3+2] Cycloaddition Reaction of 1a
or 1b with Trisubstituted Alkenes (Method C). To a mixture of
aluminum chloride (120 mg, 0.9 mmol) and 1,8-bis(dimethylamino)-
naphthalene (19.8 mg, 0.09 mmol) in CH2Cl2 (0.9 mL) was added a