9
370
S. Caddick et al. / Tetrahedron 56 (2000) 9365±9373
iodine. Sodium hydride was used as a 60% dispersion in
mineral oil. Other solvents were used as supplied (general
purpose grade). Column chromatography was performed on
Preparation of 4-hexyloxybut-1-yne 30. Sodium hydride
(1.2 g, 30.0 mmol) was added to a solution of hex-3-ynol
(2.0 g, 28.6 mmol) in dry THF (20 mL) at 08C and the
mixture was stirred for thirty minutes. t-Butylammonium
bromide (461 mg, 1.43 mmol) and hexylbromide
(4.40 mL, 30.3 mmol) were then added and the reaction
mixture heated at re¯ux for two hours. The mixture was
allowed to cool to room temperature and water (50 mL)
added. The mixture was extracted with diethyl ether
(3£100 mL) and the combined organic extracts washed
with brine (20 mL) then dried with magnesium sulfate.
The mixture was then ®ltered and the solvent removed in
vacuo. The crude product was puri®ed using ¯ash column
chromatography (3:1 petrol/diethyl ether) to give the alkyne
Ê
silica gel (70±230 mesh, 60 A). Petrol refers to petroleum
ether (boiling range: 40±608C) Thin layer chromatography
was performed on Merck silica gel 60F-254 coated plates
and visualisation was achieved using a UV lamp and/or
potassium permanganate and anisaldehyde. The term in
vacuo refers to solvent removal via rotary evaporation at
water aspirator pressure or house vacuum. All coupling
constants are given in Hertz and all melting points are
1
5
16
17±20
21
22
uncorrected. Compounds 7, 8, 13±16, 21, 22,
3, 24, 28, 36, 38, have been previously reported
2
3
24
25
26
26
2
in the literature; Compounds 1±6, 9±12, 17±20, 25, 26 can
be obtained from commercial sources.
30 as a colourless oil (3.83 g, 87%).n
1
3314, 2932, 2861,
max
2
1
116 cm ; d (CDCl ) 1.11±1.15 (3H, m, CH ), 1.51±1.61
H 3 3
Preparation of 4 hexyloxybut-2-yn-1-ol 27. Sodium
hydride (930 mg, 23.3 mmol) was added to a solution of
butane-1,4-diol (1.0 g, 11.6 mmol) in dry THF (50 mL) at
(6H, m, CH CH CH ), 1.80±1.85 (2H, m, CH ), 2.23 (1H,
2 2 2 2
t, J3.0 Hz, CCH), 2.70 (2H, dd, J7.0, 3.0 Hz, CCH ),
2
3.70 (2H, t, J7.0 Hz, CH O), 3.80 (2H, t, J7.0 Hz,
2
08C. The mixture was stirred for thirty minutes after which
the evolution of hydrogen gas had subsided. t-Butylammo-
CH O); d (CDCl ) 14.5, 20.2, 23.0, 26.2, 30.0, 32.1,
2
C
3
51.7, 69.1, 69.6, 71.6, 81.8; HRMS calculated for
C H O, 153.1357, found 153.1360 (M2H) .
1
nium bromide (747 mg, 2.3 mmol) and 1-bromohexane
(
1
0
17
3.22 mL, 35 mmol) were then added and the reaction
mixture was heated at re¯ux for two hours. The mixture
was allowed to cool to room temperature prior to addition
of water (50 mL). The mixture was extracted with ether
Preparation of 6-hexyloxyhex-2-yn-1-ol 31. n-Butyl-
lithium (2.4 mL of a 2.5 M solution in hexanes, 6.0 mmol)
was added dropwise to a solution of the alkyne 32 (1.0 g,
5.95 mmol) in dry THF (10 mL) at 08C. The reaction
mixture was stirred for thirty minutes and p-formaldehyde
(476 mg, 11.90 mmol) added. Stirring was continued for
two hours before adding aqueous ammonium chloride
(10 mL). The mixture was extracted with ether (3£30 mL)
and the extracts were combined and dried over magnesium
sulfate. The solvent was removed in vacuo and the crude
product puri®ed by ¯ash column chromatography (5:1
petrol/diethyl ether) to give the alcohol 31 as a colourless
oil (849 mg, 72%). nmax 3409, 2931, 2860, 1635, 1375,
(
3£100 mL) and the combined organic extracts dried with
magnesium sulfate. The mixture was then ®ltered and the
solvent removed in vacuo. The crude product was puri®ed
using ¯ash column chromatography (5:1 petrol/ether) to
give the alcohol 27 as a colourless oil (3.0 g, 78%). n
3
max
2
399, 2931, 2859, 1456, 1353, 1124, 1094, 1019, 733 cm ;
1
d (CDCl ) 1.06 (3H, t, J6.0 Hz, CH ), 1.49±1.58 (6H, m,
H
3
3
CH CH CH ), 1.73±1.82 (2H, m, CH ), 2.62 (1H, s,
2
2
2
2
CH OH), 3.68 (2H, t, J6.0 Hz, CH O), 4.36 (2H, s,
2
2
CH OH), 4.49 (2H, s, OCH ); d (CDCl ) 14.5, 19.1,
C
2
2
3
2
1
23.0, 29.0, 31.8, 51.8, 53.9, 78.7, 87.0, 126.3; HRMS
calculated for C H O , 169.1229, found 169.1230
1112, 1015, 910, 732 cm ; d (CDCl ) 0.82 (3H, t,
H 3
J6.0 Hz, CH ), 1.20±1.40 (6H, m, CH CH CH ), 1.49
1
0
17
2
3
2
2
2
1
M2H) .
(
(2H, t, J7.0 Hz, CH ), 1.68±1.74 (3H, m, OH and CH ),
2
2 2
2
2
.22±2.27 (2H, m, CH ), 3.34 (2H, t, J7.0 Hz, OCH ),
2 2 C
Preparation of 5-hexyloxypent-2-yne-1-ol 29. n-Butyl-
lithium (1.30 mL of a 2.5 M solution in hexanes,
3.41 (2H, t, J6.0 Hz, OCH ), 4.18 (2H, s, CH OH); d
(CDCl ) 14.5, 15.6, 23.0, 26.2, 29.1, 30.1, 32.1, 51.8,
3
1
69.6, 71.5, 78.0, 86.2; m/z (EI) 198 (M) .
3.25 mmol) was added dropwise to a solution of the alkyne
30 (500 mg, 3.25 mmol) in dry THF (10 mL) at2788C. The
reaction mixture was stirred for one hour prior to addition of
solid p-formaldehyde (195 mg, 6.50 mmol). The reaction
mixture was stirred for one hour and then allowed to
warm to room temperature, after which stirring was con-
tinued for a further hour. Aqueous ammonium chloride
solution (20 mL) was then added. The mixture was
extracted with diethyl ether (3£30 mL) and the extracts
dried over magnesium sulfate. The mixture was then ®ltered
and the solvent removed in vacuo. The crude product was
puri®ed using ¯ash chromatography (5:1 petrol/diethyl
ether) to give the alcohol 29 as a colourless oil (253 mg,
Preparation of 5-hexyloxy-1-pentyne 32. Sodium hydride
(524 mg, 13.1 mmol) was added to a solution of the pent-4-
ynol (1.00 g, 11.9 mmol) in dry THF (20 mL) at 08C. The
mixture was stirred for thirty minutes. t-Butylammonium
bromide (190 mg, 0.59 mmol) and 1-bromohexane
(1.84 mL, 13.1 mmol) was then added and the reaction
mixture heated at re¯ux for two hours. The mixture was
allowed to cool to room temperature and water was added
(50 mL). The mixture was extracted with diethyl ether
(3£100 mL) and the combined organic extracts dried with
magnesium sulfate. The mixture was then ®ltered and the
solvent removed in vacuo. The crude product was puri®ed
using ¯ash column chromatography (10:1 petrol/ether) to
4
7
1
1
2%). n
3397, 2930, 2860, 1457, 1374, 1106, 1017, 911,
max
2
1
33 cm ; d (CDCl ) 0.79 (3H, t, J7.0 Hz, CH ), 1.20±
H
3
3
.28 (6H, m, 6H, CH CH CH ), 1.44±1.50 (2H, m, CH ),
2
give the ether 32 as a colourless oil (1.76 g, 88%). n
3313, 933, 2859, 1467, 1376, 1116, 630 cm ; d
H
2
2
2
max
2
1
.89 (1H, s, OH), 2.43 (2H, t, J7.0 Hz, CH ), 3.35 (2H, t,
2
J7.0 Hz, OCH ), 3.44 (2H, t, J7.0 Hz, OCH ), 4.15 (2H,
(CDCl ) 0.73±0.79 (3H, m, CH ), 1.12±1.26 (6H, m,
3 3
2
2
s, CH OH); d (75 MHz) 14.5, 20.5, 23.0, 26.2, 23.9, 32.0,
2
CH CH CH ), 1.44 (2H, t, J7.0 Hz, CCCH ), 1.66±1.78
C
2
2
2
2
51.7, 69.2, 71.6, 79.8, 83.6; HRMS calculated for C H
NO , 202.1807, found 202.1809 (M1NH ) .
(2H, m, CH ), 1.82 (1H, t, J3.0 Hz, CCH), 2.14±2.19 (2H,
1
1
24
2
1
m, CH ), 3.28 (2H, t, J7.0 Hz, OCH ), 3.37 (2H, t,
2
4
2
2