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The Journal of Organic Chemistry
89%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.43 (t, J = 7.5 Hz, 3 H),
2.15 (s, 3 H), 1.58 (p, J = 7.2 Hz, 2 H), 1.38–1.20 (m, 12 H), 0.95–0.85 (m, 3 H).
mL), together with sodium hydride (120 mg, 3.0 mmol, 2.0 equiv, 60% dis-
persion in mineral oil) and 2-chloroethyl methyl ether (275 μL, 3.0 mmol,
2.0 equiv). The temperature was elevated and the mixture was refluxed for
2 days. Then, the reaction was carefully quenched with water (6 mL) and 1
M HCl (3 mL) and the product was extracted with ethyl acetate (3 × 6 mL).
The combined organic extracts were washed with brine (3 mL), dried over
magnesium sulfate and concentrated. Consecutive silica gel column chro-
matography (ethyl acetate/heptane 1:3) afforded ether 18 (124 mg, 47%) as
a yellow oil which was slightly contaminated with unknown impurities
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4-Methoxypentyl benzoate (16).17 Benzoyl chloride (209 μL, 1.8 mmol, 1.2
equiv) was added at 0 °C to a solution of alcohol 43 (177 mg, 1.5 mmol, 1.0
equiv), DMAP (37 mg, 0.3 mmol, 20 mol%) and triethylamine (314 μL, 2.25
mmol, 1.5 equiv) in dichloromethane (8 mL). The reaction was allowed to
warm to 20 °C and it was stirred for 15 hours. The reaction was quenched
with saturated aqueous sodium bicarbonate (5 mL), stirred for another 30
minutes and then extracted with dichloromethane (3 × 5 mL). The com-
bined organic extracts were washed with 1 M HCl (2 × 3 mL), saturated
aqueous sodium bicarbonate (3 mL) and brine (3 mL); then dried over
magnesium sulfate and the solvent was removed in vacuo to obtain ester
16 (317 mg, 95%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ 8.07–
8.02 (m, 2 H), 7.58–7.53 (m, 1 H), 7.47–7.41 (m, 2 H), 4.39–4.28 (m, 2 H),
3.42–3.32 (m, 1 H), 3.33 (s, 3 H), 1.95–1.74 (m, 2 H), 1.71–1.52 (m, 2 H), 1.17 (d,
J = 6.1 Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ 166.6, 132.8, 130.4, 129.5, 128.3,
76.3, 65.1, 56.0, 32.8, 24.8, 19.0; MS (EI+) calcd for (C13H18O3 – CH3)+ 207.102,
found 207.126; HRMS (FD+) calcd for (C13H18O3)+ 222.1256, found 222.1261.
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originating from the eluent (bottle ethyl acetate). H NMR (400 MHz,
CDCl3) δ 3.61–3.52 (m, 4 H), 3.51–3.44 (m, 2 H), 3.39 (s, 3 H), 3.31 (s, 3 H),
3.35–3.26 (m, 1 H), 1.75–1.41 (m, 4 H), 1.13 (d, J = 6.1 Hz, 3 H); 13C NMR (101
MHz, CDCl3) δ 76.6, 72.0, 71.5, 70.0, 59.1, 56.0, 32.7, 25.6, 19.0; HRMS (ESI+)
calcd for (C9H20O3 + Na)+ 199.1310, found 199.1296.
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2-(4-Methoxypentyl)isoindoline-1,3-dione (19).19 Sulfonate 44 (294 mg, 1.5
mmol, 1.0 equiv) was added to a suspension of potassium phthalimide (556
mg, 3.0 mmol, 2.0 equiv) in DMF (25 mL) and the mixture was stirred at
80 °C for 2 hours until TLC indicated full conversion of the sulfonate. Upon
completion, the mixture was cooled to 20 °C and subsequently diluted with
dichloromethane (45 mL), washed with water (2 × 45 mL) and brine (2 ×
45 mL); then dried over magnesium sulfate and the solvent was removed
in vacuo yielding a crude mixture that still contained DMF. The crude mix-
ture was redissolved in dichloromethane (30 mL) and washed with water
(2 × 15 mL) and brine (15 mL); then dried over magnesium sulfate and con-
centrated. The residue was purified with silica gel column chromatography
(ethyl acetate/heptane 1:4) to afford compound 19 (271 mg, 73%) as a trans-
parent sticky oil. 1H NMR (400 MHz, CDCl3) δ 7.87–7.81 (m, 2 H), 7.74–7.68
(m, 2 H), 3.70 (t, J = 7.3 Hz, 2 H), 3.37–3.28 (m, 1 H), 3.30 (s, 3 H), 1.86–1.66
(m, 2 H), 1.61–1.40 (m, 2 H), 1.12 (d, J = 6.1 Hz, 3 H); 13C NMR (101 MHz,
CDCl3) δ 168.4, 133.9, 132.1, 123.2, 76.2, 56.1, 38.0, 33.5, 24.7, 19.0; HRMS
(ESI+) calcd for (C14H17NO3 + Na)+ 270.1106, found 270.1080.
tert-Butyl[(4-methoxypentyl)oxy]dimethylsilane (17).18 Triethylamine (20.5
mL, 147 mmol, 3.75 equiv) was added at 0 °C to a stirring solution of TBDM-
SCl (5.9 g, 39.1 mmol, 1.0 equiv) in dichloromethane (60 mL) followed by
addition of DMAP (0.6 g, 4.91 mmol, 12.5 mol%). Then, a solution of 5-hy-
droxypentan-2-one 10 (5.0 g, 49 mmol, 1.25 equiv) in dichloromethane (15
mL) was added to the stirring mixture at the same temperature. The reac-
tion mixture was stirred for 30 min at 0 °C and then brought to 20 °C with
continued stirring for another 3 hours. The reaction mixture was then
quenched with saturated aqueous ammonium chloride (40 mL) and the
product was extracted with ethyl acetate (3 × 65 mL). The combined or-
ganic extracts were washed with water (15 mL) and brine (15 mL); then
dried over sodium sulfate and the solvent was removed in vacuo to give
the crude product (9.6 g), which was purified by flash chromatography
(ethyl acetate/heptane 1:9) to recover starting material 10 (2.33 g) and to
afford the silyl ether (3.74 g, 65% brsm) as a yellow oil. 1H NMR (400 MHz,
CDCl3) δ 3.61 (t, J = 6.1 Hz, 2 H), 2.51 (t, J = 7.3 Hz, 2 H), 2.15 (s, 3 H), 1.78
(tt, J = 7.2, 6.1 Hz, 2 H), 0.89 (s, 9 H), 0.04 (s, 6 H). Sodium borohydride
(612 mg, 16.1 mmol, 1.0 equiv) was added portion wise over 5 minutes to a
solution of the aforementioned silyl ether (3.5 g, 16.1 mmol, 1.0 equiv) in
methanol (75 mL). The reaction was stirred at 20 °C for 15 minutes and
then most methanol was evaporated under reduced pressure. Water (50
mL) was added to the residue, followed by 1N HCl to make the solution
acidic. The product was extracted with diethyl ether (3 × 20 mL). The com-
bined ethereal extracts were washed with water (10 mL) and brine (10 mL);
then dried over magnesium sulfate and the solvent was evaporated in
vacuo to afford the secondary alcohol (3.52 g, 99%) as a yellow transparent
oil. 1H NMR (400 MHz, CDCl3) δ 3.87–3.76 (m, 1 H), 3.73–3.61 (m, 2 H), 2.64
(bs, 1 H), 1.73–1.55 (m, 3 H), 1.55–1.41 (m, 1 H), 1.19 (d, J = 6.2 Hz, 3 H), 0.90
(s, 9 H), 0.07 (s, 6 H). Sodium hydride (660 mg, 16.5 mmol, 1.2 equiv, 60%
dispersion in mineral oil) was added at 0 °C to a solution of the aforemen-
tioned secondary alcohol (3.00 g, 13.7 mmol, 1.0 equiv) in THF (20 mL). The
mixture was stirred for 15 minutes and then methyl iodide (1.03 mL, 16.5
mmol, 1.2 equiv) was added. The mixture was allowed to warm to 20 °C and
it was stirred for 18 hours. Then, the reaction was quenched with aqueous
sodium thiosulfate (5% in water, 30 mL) and the product was extracted
with ethyl acetate (3 × 30 mL), washed with brine (15 mL), then dried over
magnesium sulfate and concentrated. Silica gel column chromatography
(pentane → ethyl acetate) yielded substrate 17 (3.05 g, 95%) as a transpar-
ent yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.67–3.57 (m, 2 H), 3.31 (s, 3 H),
3.35–3.27 (m, 1 H), 1.65–1.39 (m, 4 H), 1.13 (d, J = 6.1 Hz, 3 H), 0.89 (s, 9 H),
0.05 (s, 6 H); 13C NMR (101 MHz, CDCl3) δ 76.6, 63.2, 55.9, 32.5, 28.7, 26.0,
19.1, 18.4, –5.3; MS (ESI+) calcd for (C12H28O2Si + H)+ 233, found 233. HRMS
(FI+) calcd for (C12H28O2Si – C4H9)+ 175.1154, found 175.1160.
5-Methoxyhexanenitrile (20).20,21 Sodium cyanide (221 mg, 4.5 mmol, 3.0
equiv) was added to a solution of sulfonate 44 (294 mg, 1.5 mmol, 1.0 equiv)
in DMSO (12 mL) and the mixture was stirred at 80 °C for 2.5 hours, and
subsequently cooled to 20 °C. Then, the reaction was carefully quenched
with water (60 mL), and the reaction mixture was extracted with ethyl ac-
etate (3 × 40 mL). The combined organic extracts were washed with brine
(2 × 20 mL), dried over sodium sulfate and concentrated. Purification by
silica gel column chromatography (dichloromethane) afforded nitrile 20
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(130 mg, 68%) as a yellow liquid. H NMR (400 MHz, CDCl3) δ 3.39–3.30
(m, 1 H), 3.32 (s, 3 H), 2.46–2.28 (m, 2 H), 1.86–1.64 (m, 2 H), 1.62–1.56 (m,
2 H), 1.15 (d, J = 6.1 Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ 119.7, 75.8, 56.0,
35.3, 21.5, 18.9, 17.2; MS (EI+) calcd for (C7H13NO – CH3)+ 112.076, found
112.089.
4-Methoxy-1-(piperidin-1-yl)pentan-1-one (21).22 Trimethylaluminum (2 M
in toluene, 2.5 mL, 5 mmol, 2 equiv) was added at –78 °C to a 1 M solution
of freshly distilled piperidine (1.25 mL, 12.5 mmol, 5 equiv) in THF (12.5 mL)
and the resulting mixture was stirred at –78 °C for 30 minutes. Then, a
solution of γ-valerolactone 45 (0.24 mL, 2.5 mmol, 1 equiv) in THF (6 mL)
was added dropwise to the stirring piperidine solution after which the re-
action mixture was allowed to warm to 20 °C. Stirring was continued for
another 1.5 hours before the reaction was quenched by careful addition of
dichloromethane (25 mL) and 0.1 M HCl (50 mL). The product was ex-
tracted with dichloromethane (5 × 10 mL) and the combined organic ex-
tracts were washed with 1 M HCl (25 mL), dried over magnesium sulfate
and the solvent was removed in vacuo to afford alcohol intermediate as a
sticky yellow liquid. Then, the alcohol was redissolved in THF (5 mL) and
to this solution sodium hydride (120 mg, 3.0 mmol, 1.2 equiv, 60% disper-
sion in mineral oil) was added at 0 °C. The mixture was stirred for 30
minutes and then methyl iodide (188 μL, 3.0 mmol, 1.2 equiv) was added.
The mixture was allowed to warm to 20 °C and it was stirred for 2 hours.
Then, the reaction was quenched with aqueous sodium thiosulfate (5% in
water, 8 mL) and the product was extracted with ethyl acetate (3 x 10 mL),
washed with brine (5 mL), dried over magnesium sulfate and concentrated.
Silica gel column chromatography (ethyl acetate) yielded ether 21 (408 mg,
82% over 2 steps) as a transparent yellow oil. 1H NMR (400 MHz, CDCl3) δ
3.59–3.51 (m, 2 H), 3.44–3.40 (m, 2 H), 3.40–3.33 (m, 1 H), 3.32 (s, 3 H), 2.43
(ddd, J = 15.3, 9.2, 6.0 Hz, 1 H), 2.36 (ddd, J = 15.4, 9.0, 6.5 Hz, 1 H), 1.85
(dddd, J = 13.7, 9.2, 6.5, 4.4 Hz, 1 H), 1.74 (dddd, J = 14.1, 9.1, 7.4, 6.0 Hz, 1
H), 1.68–1.60 (m, 2 H), 1.60–1.49 (m, 4 H), 1.15 (d, J = 6.2 Hz, 3 H); 13C NMR
4-Methoxy-1-(2-methoxyethoxy)pentane (18). Sodium hydride (72 mg, 1.8
mmol, 1.2 equiv, 60% dispersion in mineral oil) was added at 0 °C to a so-
lution of compound 43 (177 mg, 1.5 mmol, 1.0 equiv) in THF (4 mL). The
mixture was stirred for 30 minutes and then 2-chloroethyl methyl ether
(164 μL, 1.8 mmol, 1.2 equiv) was added. Stirring was continued for 2 hours,
while no conversion was observed. Sodium iodide (22 mg, 0.15 mmol, 10
mol%) was added to catalyze the reaction. After stirring for another 16
hours, conversion was barely observed so additional THF was added (5
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