P.J. Parsons et al. / Tetrahedron 66 (2010) 6526e6533
6531
residue was purified using flash column chromatography (gradient;
1:3 diethyl ether/pentane to diethyl ether 100%) to yield 12 (62 mg
22%) as an off white solid. Using heat in benzene: A solution of N-
{4-[2-bromoprop-2-en-1-yl)phenyl]-4-hydroxybut-2-yn-1-yl}-N-
methyl-3-(trimethylsilyl)prop-2-ynamide 10 (0.50 g, 1.2 mmol) in
benzene (30 ml) was heated at reflux for 40 h. Solvent was removed
under reduced pressure, hexane added to the residue and the
precipitate purified by filtration and washing with diethyl ether
and hexane to yield 12 (202 mg, 50%). Using heat in toluene: A
solution of N-{4-[2-bromoprop-2-en-1-yl)phenyl]-4-hydroxybut-
2-yn-1-yl}-N-methyl-3-(trimethylsilyl)prop-2-ynamide 10 (0.50 g,
1.2 mmol) and butyl oxirane (2.9 ml, 23.9 mmol) in toluene (10 ml)
was heated at reflux for 3 h. Solvent was removed under reduced
pressure and the residue purified using flash column chromatog-
raphy (gradient; diethyl ether/hexane 1:1. 2:1, 4:1, 1:0, then 1:1
diethyl ether/THF) to yield 12 (207 mg, 76%). IR (Nujol) v, (cmꢀ1):
3043, 2955, 2925, 2868, 2855, 1943, 1921, 1647, 1570, 1501, 1487,
1463, 1442, 1416, 1403, 1371, 1336, 1286, 1247, 1219, 1162, 1147, 1118,
1084, 1028, 905, 868, 854, 835, 747, 721. dH (300 MHz, DMSO-d6):
9.79 (br s, 1H, 19-OH), 8.22e8.19 (d, 1H, J¼8.6 Hz, Ar), 7.74.7.71 (m,
1H, Ar), 7.34e7.41 (m, 2H, Ar), 7.26 (s, 1H, Ar, 6-CH), 4.82e4.35 (dd,
2H, J1¼20.1 Hz, J2¼122.3 Hz, 16-CH2), 3.29e3.22 (m, 2H, 4-CH2),
3.09e2.96 (m, 3H, NeMe), 2.20 (d, 1H, J¼7.3 Hz, 3-CH), ꢀ0.19 (s, 9H,
17-3CH3). dC (75 MHz, DMSO-d6): 169.7 (q, 1-C), 148.3 (q), 141.6 (q),
135.6 (q), 134.2 (q), 133.9 (q), 127.3 (CH, Ar), 126.5 (CH, Ar), 124.8 (q),
124.7 (CH, Ar), 122.2 (CH, Ar, 114.9 (q) 54.7 (CH2, 16-C), 31.1 (CH2, 4-
C), 28.8 (CH3, 18-C), 21.2 (CH, 3-C), ꢀ2.1 (3CH3, 17-C). MS (EI) m/z
(rel int.): 360, 338, 322, 232. HRMS (ESIþ): calcd for C20H23NO2SiNa,
m/z 360.1390, found 360.1388. calcd for C20H24NO2Si, m/z 338.1571,
found 338.1566.
stirred for 30 min. A solution of 2-[3-(trimethylsilyl)prop-2-yn-1-
yl] benzaldehyde 16 (2.50 g, 11.56 mmol) in THF (5 ml) was added
dropwise and the reaction mixture allowed to stir for 60 min. The
reaction was quenched with 2-bromo-2-methylpropane (2.0 ml,
17.33 mmol) and allowed to slowly warm to room temperature. The
reaction mixture was diluted with diethyl ether (2ꢂ150 ml). The
combined organic phases were washed with brine, dried over
magnesium sulfate, filtered and the solvent removed under re-
duced pressure to give a dark orange oil. This was purified using
flash column chromatography (3:2 hexane/diethyl ether) to yield
17 (4.01 g, 90%) as a transparent yellow oil. IR (neat) v (cmꢀ1): 3396,
2963, 2931, 2248, 2177, 1678, 1483, 1455, 1393, 1368, 1251, 1152,
1026, 954, 911, 844, 759, 734. dH (300 MHz, CDC13): 7.66 (m, 1H, Ar),
7.49e7.46 (m, 1H, Ar), 7.34e7.28 (m, 2H, Ar), 5.71 (s, 1H, 10-CH), 4.11
(br s, 2H, 13-CH2), 3.82 (s, 2H, 11e3-CH2), 2.90 (s with long tail, 4H,
14-CH3 and 19-OH), 1.44 (s, 9H, 17.3CH3), 0.17 (s, 9H, 3CH3). dC
(75 MHz, CDC13): 155.2 (q, 15-C), 137.8 (q, Ar), 134.2 (q, Ar), 129.3
(CH, Ar), 127.3 (2CH, 2Ar), 104.2 (q, alkyne), 87.7 (q, alkyne),
82.5e82.2 (q, alkyne), 80.2 (q, 16-C), 62.1 (CH, 10-C), 38.6e37.9
(CH2, br d, 13-C), 33.6 (CH3, 14-C), 28.3 (3CH3, 17-C), 23.5 (CH2, 3-C),
ꢀ0.03 (3CH3, 18-C). MS (EI) I (rel int.): 410, 409, 408, 354, 353, 352,
136. HRMS (ESIþ): calcd for C22H31NO3SiNa, m/z 408.1965, found
408, 1958.
3.1.10. tert-Butyl[4-hydroxy-4-(2-prop-2-yn-1-yl-phenyl)but-2-yn-
1-yl]methylcarbamate (17a). A solution of tert-butyl[4-hydroxy-4-
(2-prop-2-yn-1-yl-phenyl)but-2-yn-1-yl]methylcarbamate
17
(2.53 g, 6.7 mmol) and sodium methoxide (0.11 g, 1.97 mmol) in
DCM (10 ml) and MeOH (10 ml) was stirred at room temperature
for 18 h, diluted with DCM (20 ml), washed with water and the
aqueous fractions extracted with DCM (2ꢂ20 ml). The combined
organic fractions were dried over magnesium sulfate, filtered and,
the solvent removed under reduced pressure to yield 17a (2.04 g,
97%) as a yellow oil. IR (neat) v (cmꢀ1): 3396, 3303, 2977, 2929,
2248, 2120, 1677, 1483, 1455, 1421, 1393, 1368, 1251, 1152, 1050,
1029, 1004, 872, 755. dH (300 MHz, CDC13): 7.66e7.63 (d, 1H,
J¼6.9 Hz, Ar), 7.53e7.51 (d, 1H, J¼6.8 Hz, Ar), 7.36e7.29 (m, 2H, Ar),
5.73e5.71 (d, 1H, J¼4.3 Hz, 10-CH), 4.12 (br s, 2H, 13-CH2), 3.80 (s,
2H, 3-CH2), 2.91 (s, 3H, 14-CH2), 2.46 (br s 1H, 18-OH), 2.23e2.21 (t,
1H, J¼1.4 Hz, 1-CH), 1.45 (s, 9H, 17.3CH3). dC (75 MHz, CDC13): 155.2
(q, 15-C), 137.7 (q. Ar), 134.0 (q, Ar), 129.2 (CH, Ar), 128.7 (CH, 2Ar),
127.2 (CH, Ar), 127.1 (CH, Ar), 82.6 (q, alkyne), 82.2 (q, alkyne), 81.7
(q, alkyne), 80.2 (q, 16-C), 71.1 (CH2, 1-C), 62.1 (CH, 10-C), 38.6e37.9
(CH2, br d, 13-C), 33.6 (CH3, 14-C), 28.3 (3CH2, 17-C), 21.9 (CH2, 3-C).
MS (EI) m/z (rel int.): 336, 330, 280, 112, 101, 58. HRMS (ESIþ): calcd
for C19H23NO3Na, m/z 336.1570, found 336.1552.
3.1.8. 2-[3-(Trimethylsilyl)prop-2-yn-1-yl]benzaldehyde
(16). n-
Butyllithium (8.23 ml, 20.58 mmol) was added dropwise to
a cooled (CO2/acetone) solution of 2-(2-bromophenyl)-1,3-dime-
thylimidazolidine 7 (5.0 g, 19.60 mmol) in THF (100 ml) and the
reaction mixture stirred for 20 min. Copper cyanide (1.84 g,
20.58 mmol) was added and the reaction mixture allowed to
warm to 30 ꢁC and stirred at this temperature for 45 min. The
reaction mixture was again cooled fully and 3-(trimethylsilyl)
propargyl bromide (3.43 ml, 21.56 mmol) added. The reaction
mixture was allowed to warm slowly to room temperature and
quenched with saturated ammonium chloride solution (50 ml).
The reaction mixture was extracted with diethyl ether (2ꢂ150 ml),
the combined organic fractions washed with hydrochloric acid
(2 M, 3ꢂ100 ml with vigorous shaking), saturated sodium hydro-
gen carbonate solution and brine, dried over magnesium sulfate,
filtered and the solvent removed under reduced pressure to give
€
a red oil. This was purified using Kugelrohr distillation (0.09 mbar,
3.1.11. 4-(Methylamino)-1-(2-prop-2-yn-1-yl-phenyl)but-2-1-ol-hy-
140e150 ꢁC) to yield 16 (2.9 g, 69%) as a clear colourless oil. IR
(neat) v (cmꢀ1): 3377, 3071, 2961, 2899, 2834, 2737, 2488, 2343,
2178, 1947, 1695, 1601, 1576, 1487, 1454, 1406, 1320, 1295, 1251,
1198, 1105, 1030, 958, 843, 758, 701, 646. dH (300 MHz, CDC13):
10.21 (s, 1H, 10-CH), 7.82e7.79 (d, 1H, J¼7.6 Hz, Ar), 7.74e7.72 (d,
1H, J¼7.6 Hz, Ar), 7.62e7.57 (m, 1H, Ar), 7.48e7.43 (t, 1H, J¼7.4 Hz,
Ar), 4.11 (s, 2H, 3-CH2), 0.18 (s, 9H, 11-3CH3). dC (75 MHz, CDC13):
192.7 (CH, 10-C), 138.3 (q, Ar), 134.O (CH, Ar), 133.4 (CH, Ar), 133.1
(q, Ar), 129.7 (CH, Ar), 127.2 (CH, Ar), 103.3 (q, alkyne), 88.5 (q,
alkyne), 23.9 (CH2, 3-C), 0.02 (3CH3, 11-C). MS (EI) m/z (rel int.):
239, 217, 102, 79. HRMS (ESIþ): calcd for C13H16OSiNa, m/z
239.0863, found 239.0861.
drochloride (17b). A solution of tert-butyl[4-hydroxy-4-(2-prop-2-
yn-1-yl-phenyl)but-2-yn-1-yl]methylcarbamate
17a
(0.78 g,
2.5 mmol) and hydrochloride acid in diethyl ether (2 M, 2.5 ml,
5.0 mmol) was stirred at room temperature for 3.5 h. Pentane
(7 ml) was added and the precipitate removed by filtration. The
filter cake was washed with diethyl ether and pentane and sucked
dry under nitrogen to yield 17b (0.37 g, 60%) as an off white solid,
mp 96e100 ꢁC. IR (neat) v (cmꢀ1): 3584, 3303, 3246, 2954, 2925,
2855, 2727, 2561, 2490, 2467, 2397, 1602, 1461, 1398, 1377, 1301,
1205, 1116, 1096, 1021, 795, 749. dH (300 MHz, DMSO-d6): 9.48 (br s,
2H, NH2), 7.62e7.60 (d, 1H, J¼6.3 Hz, Ar), 7.50.7.48 (d, 1H, J¼6.5 Hz,
Ar), 7.34e7.28 (m, 2H, Ar), 6.28 (br s, 1H, 16-OH), 5.65 (s, 1H, 10-CH),
3.91 (s, 2H, 13-CH2), 3.90 (s, 2H, 3-CH3), 3.15 (s, 1H, 1-CH), 2.52 (s,
3H,14-CH3). dC (75 MHz, DMSO-d6): 138.5 (q, Ar),133.7 (q, Ar),128.4
(CH, Ar), 128.0 (CH, Ar), 126.7 (2CH, 2Ar), 88.2 (q, alkyne), 81.8 (CH,
1-C), 78.0 (q, alkyne), 73.9 (q, alkyne), 59.9 (CH, 10-C), 36.8 (CH2, 13-
C), 31.3 (CH3, 14-C), 21.0 (CH2, 3-C). MS (EI) m/z (rel int.): 213, 194,
181, 165, 153, 141, 128, 115, 103, 94, 77, 68, 44. MS (EI) m/z (rel int.):
3.1.9. tert-Butyl(4-hydroxy-4-{2-[3-(trimethylsilyl)prop-2-yn-1-yl]
phenyl}but-2-yn-1-yl)methylcarbamate
(17). n-Butyllithium
(5.1 ml, 12.71 ml) was added (reaction mixture <ꢀ90 ꢁC through-
out) to a cooled (N2/methanol) solution of tert-butyl methyl(prop-
2-yn-1-yl)carbamate (2.15 g, 12.7 mmol) in THF (200 ml) and