E. Hedenstro¨m et al. / Tetrahedron: Asymmetry 13 (2002) 835–844
841
4.6. Methyldecanoic acid 5
with HCl (conc.). Extraction of this water phase with
Et2O (3×100 mL), drying (MgSO4) and evaporation of
the solvent gave a yellow oil, which was distilled to
yield the title acid 5 (1.77 g, 9.52 mmol) with >99.0%
purity by GC. Bp 97°C/0.5 mbar (lit.52 157–158°C/10
4.6.1. 1-Bromo-2-methylpentane. The procedure used
above for the preparation of 1-bromo-2-methylhexane,
was applied starting from 2-methyl-1-pentanol (49.7 g,
487 mmol). After distillation at atmospheric pressure a
main fraction at 145°C (lit.45 51°C/52 Torr) of a colour-
1
Torr). H NMR l: 0.85 (3H, d, J=6.4 Hz), 0.88 (3H,
t, J=6.9 Hz), 1.05–1.19 (2H, m), 1.21–1.40 (2H, m),
1.62–1.68 (2H, m); 2.36 (2H, t, J=7.7 Hz). 13C NMR
l: 14.4, 19.6, 20.1, 24.7, 26.8, 29.5, 32.4, 34.0, 36.9,
39.3, 180.1.
1
less oil (67.9 g, 414 mmol) pure by GC. The IR and H
NMR spectra were similar to those reported.46,47
4.6.2. 4-Methylheptanoic acid. A malonic ester sequence
(see above) but starting from 1-bromo-2-methylpentane
(67.3 g, 408 mmol) gave 4-methylheptanoic acid (42.3 g,
294 mmol) in >99% purity by GC. The IR and 1H
NMR spectra were similar to those reported.48
4.7. 8-Methyldecanoic acid 6
4.7.1. Ethyl b-methyl-5-(1-(2-methyl)butyl)-2-thiophene
acetate 16. Freshly distilled ethyl 2-thiopheneacetate
(7.91 g, 46.5 mmol), 2-methylbutanoyl chloride (5.02 g,
41.7 mmol) and dry CH2Cl2 (150 mL). Into this stirred
mixture was at 0°C SnCl4 (150 mL, 140 mmol) was
added dropwise. After 2.5 h, 6 M HCl (50 mL) was
added, then followed extraction with Et2O (3×50 mL),
washing with brine (100 mL), drying (MgSO4), filtra-
tion and concentration to give a crude product. After
LC and distillation (145°C/1.5 mbar) the acylated com-
pound (8.05 g, 31.7 mmol) in >99% purity by GC was
obtained. m/z (relative intensity) 254 (M+, 12%), 226
(15), 197 (100), 169 (30), 147 (5), 124 (12), 96 (15), 73
4.6.3. 4-Methyl-1-heptanol. 4-Methylheptanoic acid
(26.6 g, 180 mmol) was reduced using LiAlH4 (see
above) and gave 4-methyl-1-heptanol (21.1 g, 162
mmol) with a chemical purity of >99,7% by GC. The
IR and 1H NMR spectra were similar to those
reported.48
4.6.4. 1-Bromo-4-methylheptane 14. 4-Methyl-2-hep-
tanol (9.70 g, 74.6 mmol) was reacted with Ph3PBr2 as
described above and this gave (12.2 g, 63.4 mmol) of
the title product with a chemical purity of >99.5% by
1
(20). H NMR l: 0.92 (3H, t, J=7.4 Hz), 1.20 (3H, d,
J=6.9 Hz), 1.29 (3H, t, J=7.1 Hz), 1.42–1.59 (1H, m),
1.74–1.90 (1H, m), 3.13–3.24 (1H, m), 4.16–4.25 (2H, q,
J=7.1 Hz), 6.98–7.00 (1H, dt, J=0.8 and 3.8 Hz), 7.59
(1H, d, J=3.8 Hz). 13C NMR l: 11.9, 14.1, 14.2, 17.3,
27.1, 36.1, 43.8, 61.6, 128.0, 131.5, 143.8, 144.1, 169.5,
197.2. HRMS calc. for C13H18O3S: 254.0977. Obs:
254.0964.
1
GC. The identity of the bromide was checked with H
NMR and directly used in the next step below.
4.6.5. 1-Lithio-4-methylheptane. Lithium metal (4.99 g,
720 mmol) was cut into pieces into dry hexane,49 the
mixture was heated under reflux for 0.5 h and 1-bromo-
4-methylnonane 14 (7.00 g 36.0 mmol) in dry hexane (7
mL) was added dropwise over 1.25 h. The reflux was
continued for 0.5 h after the addition was completed.
4.7.2. Ethyl b-methyl-5-(2-methylbutanoyl)-2-thiophene
acetate 17. Using the method of Di Vona and Rosnati53
the acetate from above (6.50 g, 25.6 mmol) was added
to a slurry of amalgamated zinc54 (16.0 g) in acetic acid
(250 mL) at room temperature. After 12 h, the catalytic
amalgam was filtered off and washed with n-pentane
(2×50 mL). Then water (250 mL) was added and after
extraction with n-pentane (5×200 mL) the organic
phase was washed with NaHCO3 (200 mL, satd aq.),
the organic phase was then dried (MgSO4) and concen-
trated. The crude product was purified by LC to afford
compound 17 (5.04 g, 23.6 mmol, 99% pure by GC). Bp
4.6.6. Dilithium methyl-(4-methyl-heptyl)-cyanocuprate.
Similarily prepared as in the literature for other
cyanocuprates.50 Methyllithium (36.0 mmol, 23.0 mL
1.5 M solution in Et2O) was added to a suspension of
cuprous cyanide (3.22 g, 36.0 mmol, dried in an oven at
105°C and further dried by mixing with dry toluene at
room temperature followed by evaporation at reduced
pressure). The solid was suspended in dry n-hexane (50
mL) at –60°C. The mixture was stirred for 1 h and then
allowed to warm to 0°C, again cooled to –60°C and at
that temperature the solution of 1-lithio-4-methylhep-
tane from above was slowly added.
1
145°C/0.63 mbar. H NMR l: 0.90 (3H, d, J=6.6 Hz),
0.90 (3H, t, J=7.3 Hz), 1.09–1.30 (1H, m), 1.27 (3H, t,
J=7.1 Hz), 1.31–1.48 (1H, m), 1.57–1.68 (1H, m),
2.51–2.60 (1H, dd, J=7.7 and 14.5 Hz), 2.71–2.79 (1H,
dd, J=6.1 and 14.5 Hz), 3.75 (2H, d, J=0.7 Hz), 4.18
(2H, q, J=7.1 Hz), 6.58–6.60 (1H, dt, J=0.8 and 3.4
Hz), 6.71–6.74 (1H, dt, J=0.9 and 3.4 Hz). 13C NMR
l: 11.4, 14.2, 19.0, 29.0, 35.8, 36.9, 37.3, 61.1, 124.6,
126.3, 132.7, 144., 170.7. HRMS calc. for C13H20O2S:
240.1184. Obs: 240.1171.
Following the method reported by Christenson et al.,51
to the resulting mixture methyl acrylate (3.10 g, 36.0
mmol) dissolved dry n-hexane (3 mL) was added drop-
wise at –60°C. The mixture was stirred overnight and
allowed to reach room temperature. After addition of
NH4Cl (satd in conc. ammonia) the organic layer was
separated and the blue aqueous layer extracted with
Et2O (3×100 mL). The combined organic phases were
washed with water (100 mL), brine (100 mL) and dried
(MgSO4). Evaporation of the solvent gave a brown oil
which was subjected to hydrolysis in KOH solution (2.5
M, ethanol). The reaction mixture was then washed
with Et2O (100 mL) and the water phase was acidified
The acetate from above (4.80 g, 22.4 mmol) was dis-
solved in isopropanol (80 mL), Raney-Ni (12 tea-
spoons) was added and then the slurry was stirred
under H2 for 48 h. The Raney-Ni was filtered off,
rinsed with EtOH (95%, 4×100 mL) and then the
solvent was evaporated off. Without further purifica-
tion this crude product was dissolved in a solution of 3