In a further experiment the crude reaction mixture
obtained by coupling of 9 (16 g) and 10 (14 mL) was purified
without chromatography by two crystallizations (hexane-
acetate 1:3, 2 × 80 mL) to give 11.6 g of 11 (94% GC,
72% yield).
Coupling Experiments between 5 and 10: 4,4-Dimethyl-
6-bromothiochromane 5 (3 g) and 2-methyl-3-butyn-2-ol 10
(10 mL) were coupled using the experimental condi-
tions described for 9/10 coupling and 8/12 coupling. The
GC-MS analyses of the crude reaction mixtures do not
evidence the presence of the expected coupling product.
6-[2-(4,4-Dimethylthiochroman-6-yl)ethynyl]nicotinic
Acid Ethyl Ester (1). PCl3 (6.9 mL, 79.0 mmol) was added
dropwise to a stirred solution of 15 (29.0 g, 79.0 mmol) in
N,N-dimethylformamide (300 mL) at -20 °C. After 1 h, the
mixture was warmed to rt, diluted with ethyl acetate (400
mL), and washed with 5% NaHCO3 solution (200 mL), water
(200 mL), and brine (200 mL). The organic phase was dried
(Na2SO4) and concentrated under reduced pressure. The
residue was purified by chromatography (hexane/acetate 9:1)
and crystallization from hexane (100 mL) to afford pure
(99% GC) 1 (16.4 g, 59% yield); mp 97-98 °C); 1H NMR
δ 1.34 (6H, s), 1.42 (3H, t, J ) 7.1 Hz), 1.96 (2H, m), 3.05
(2H, m), 4.42 (2H, q, J ) 7.1 Hz), 7.08 (1H, d, J ) 8.0 Hz),
7.25 (1H, dd, J ) 1.8, 8.0 Hz), 7.55 (1H, d, J ) 8.0 Hz),
7.62 (1H, d, J ) 1.8 Hz), 8.26 (1H, dd, J ) 2.1, 8.0 Hz),
9.23 (1H, d, J ) 2.1 Hz); 13C NMR δ 13.9, 22.9, 29.5, 29.5,
32.6, 36.7, 61.1, 87.7, 92.7, 116.5, 124.2, 125.9, 126.3, 129.0,
130.0, 134.7, 136.6, 141.8, 146.8, 150.7, 164.4; IR (Nujol)
cm-1 2202, 1720, 1586, 1377, 1287, 1269, 1155, 1134, 1107,
1056, 1025, 851, 824, 778; EI-MS (m/z) 353 (5), 352 (22),
351 (100), 336 (17), 309 (5), 308 (29), 293 (6), 262 (5), 185
(3), 84 (7). Anal. Calcd for C21H21NO2S: C, 71.76; H, 6.02;
N, 3.99; S, 9.12. Found: C, 71.80; H, 6.00; N, 4.00; S, 9.10.
6-[(3-Methyl-3-hydroxy)but-1-yn]nicotinic Acid Ethyl
Ester (13). To a solution of 8 (7.0 g, 37.8 mmol) in DME
(200 mL) was added water (90 mL), K2CO3 (20.85 g, 150.9
mmol), CuI (0.29 g, 1.5 mmol), Ph3P (0.79 g, 3 mmol), and
10% Pd/C (0.80 g, 0.75 mmol). The resulting mixture was
stirred at rt for 30 min, and then 2-methyl-3-butyn-2-ol 10
(14.7 mL, 151 mmol) was added and the reaction warmed
at 80 °C for 3 h. The mixture was cooled to rt and filtered
on a Celite pad washing with ethyl acetate. The solution was
diluted with water (400 mL) and extracted with ethyl acetate
(2 × 300 mL). The organic phase was washed with brine
(150 mL), dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by chromatography eluting
with hexanes-ethyl acetate 9:1 to afford pure (96% GC) 13
4,4-Dimethyl-6-ethynylthiochromane S-Oxide (12). NaH
(400 mg of a 60% dispersion in mineral oil, 10 mmol)
was added to a stirred solution of 11 (32.86 g, 119 mmol)
in dry toluene (400 mL). The suspension was slowly dis-
tilled until about 200 mL of the toluene/acetone mixture
were collected. The residue was cooled and concentrated
under reduced pressure. The obtained solid was dissolved
in diethyl ether (400 mL), and the mixture was washed with
1 M Na2CO3 solution (100 mL), water (60 mL), and brine
(100 mL). The organic phase was dried (Na2SO4) and
concentrated under reduced pressure to give 12 (95% GC,
1
21.7 g, 84% yield); mp 105-107 °C; H NMR δ 1.32
(3H, s), 1.45 (3H, s), 1.88 (1H, ddd, J ) 2.5, 8.8, 15.1 Hz),
2.44 (1H, ddd, J ) 2.5, 10.3, 15.1 Hz), 3.08 (1H, ddd,
J ) 2.5, 8.8, 13.1 Hz), 3.17 (1H, s), 3.19 (1H, m), 7.46
(1H, dd, J ) 1.5, 8.1 Hz), 7.56 (1H, d, J ) 1.5 Hz), 7.71
(1H, d, J ) 8.1 Hz); IR (Nujol) cm-1 3206, 2102, 1593,
1544, 1409, 1110, 1030, 827; EI-MS (m/z) 218 (8), 201
(100), 187 (11), 175 (23), 173 (49), 159 (17), 147 (5), 139
(9), 129 (11), 115 (18), 102 (3), 89 (5). Anal. Calcd for
C13H14OS: C, 71.52; H, 6.46; S, 14.69. Found: C, 71.45;
H, 6.50; S, 14.75.
6-[2-(4,4-Dimethylthiochroman-6yl)ethynyl]nicotinic
Acid Ethyl Ester S-Oxide (15) via Coupling of 8 and 12.
(Ph3P)2PdCl2 (5.93 g, 8.5 mmol) and CuI (2.37 g, 12.4 mmol)
were added under nitrogen to a solution of 8 (21.24 g, 114.5
mmol), triethylamine (60 mL), and 12 (21,7 g, 99.5 mmol)
in N,N-dimethylformamide (400 mL). The mixture was
warmed to 50 °C and stirred until no more starting 12 was
detected by TLC analysis (3 h). After cooling to rt the
reaction was diluted with ethyl acetate (600 mL) and washed
with water (3 × 300 mL). The aqueous phases were extracted
again with ethyl acetate (2 × 200 mL), and the combined
organic phases were washed with brine (200 mL), dried
(Na2SO4), and concentrated under reduced pressure. The
residue was purified by chromatography (hexane/acetate 5:2)
and crystallization from a mixture of hexane (90 mL) and
ethyl acetate (10 mL) to afford pure (98% GC) 15 (29.0 g,
79% yield); mp 144-146 °C; 1H NMR δ 1.34 (3H, s), 1.43
(3H, t, J ) 7.1 Hz), 1.48 (3H, s), 1.91 (1H, ddd, J ) 2.4,
8.9, 15.1 Hz), 2.45 (1H, ddd, J ) 2.4, 10.1, 15.1 Hz), 3.16
(2H, m), 4.45 (2H, q, J ) 7.1 Hz), 7.58 (1H, dd, J ) 1.6,
8.1 Hz), 7.62 (1H, m), 7.71 (1H, d, J ) 1.6 Hz), 7.78 (1H,
d, J ) 8.1 Hz), 8.31 (1H, dd, J ) 2.1, 8.1 Hz), 9.23 (1H,
m); IR (Nujol) cm-1 2210, 1723, 1589, 1376, 1292, 1134,
1114, 1034, 827, 779. Anal. Calcd for C21H21NO3S: C,
68.64; H, 5.76; N, 3.81; S, 8.73. Found: C, 68.60; H, 5.75;
N, 3.75; S, 8.75.
1
as a pale yellow oil (6.1 g, 69% yield); H NMR δ 1.40
(3H, t, J ) 7.1 Hz), 1.65 (6H, s), 4.40 (2H, q, J ) 7.1 Hz),
7.50 (1H, dd, J ) 0.7, 8.0 Hz), 8.20 (1H, dd, J ) 2.1, 8.0
Hz), 9.10 (1H, dd, J ) 0.7, 2.1 Hz); IR (neat) cm-1 3375,
2235, 1724, 1593, 1557, 1471, 1373, 1285, 1269, 1172, 1114,
1025, 968, 913, 856, 780, 730; EI-MS (m/z) 233 (3), 218
(75), 204 (2), 190 (100), 174 (5), 162 (38), 148 (81), 130
(14), 117 (23), 102 (27), 89 (12), 75 (22). Anal. Calcd for
C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.05;
H, 6.45; N, 6.05.
In a further experiment the crude reaction mixture
obtained by coupling of 8 (40 g) and 12 (40 g) was purified
without chromatography by two crystallizations (hexane-
acetate 9:1, 2 × 160 mL) to give 41.2 g of 15 (94% GC,
61% yield).
6-Ethynylnicotinic Acid Ethyl Ester (14). NaH (100 mg
of a 60% dispersion in mineral oil, 2.5 mmol) was added to
a stirred solution of 13 (6.86 g, 29.4 mmol) in dry toluene
(200 mL). The suspension was slowly distilled until about
100 mL of the toluene/acetone mixture were collected. The
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