S. Fuse, H. Yoshida, K. Oosumi, T. Takahashi
FULL PAPER
temperature under Ar. After having been stirred at 80 °C for 12 h,
the reaction mixture was poured into 1 m HCl, and the aqueous
layer was extracted with ethyl acetate. The combined organic layers
were washed with saturated aqueous NaHCO3 and brine, dried
with MgSO4, and filtered. After removal of the solvent, the residue
was purified by column chromatography on silica gel (0–10% ethyl
acetate in hexane) to give (E)-2,2-dimethyl-5-(thiophen-2-yl)-6-[2-
1.45 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.9, 168.4,
167.2, 141.2, 134.7, 130.8, 129.5, 129.0, 128.3, 127.9, 127.6, 127.1,
119.5, 97.4, 82.4, 42.0, 28.0 ppm. IR (neat): ν = 3407, 2926, 1739,
˜
1624, 1527, 1369, 1261, 1156, 703 cm–1. HRMS (ESI-TOF): calcd.
for C19H22NO4S2 [M + H]+ 392.0990; found 392.0990.
General Procedure for the Nucleophilic Addition of Amines to In
Situ Generated Ketene from the Dioxinone Scaffold: The amine
(1.0–3.0 equiv.) was added to a solution of dioxinone (1.0 equiv.)
in toluene at room temperature in a sealed tube. The mixture was
stirred at reflux for the stated time, then it was poured into H2O,
and the aqueous layer was extracted with ethyl acetate. The com-
bined organic layers were washed with brine, dried with MgSO4,
and filtered. The solvent was removed, and the residue was purified
by column chromatography on silica gel to give the β-keto amide.
(thiophen-2-yl)vinyl]-4H-1,3-dioxin-4-one
(12;
12.1 mg,
0.038 mmol, 91%) as a yellow solid. 1H NMR (400 MHz, CDCl3):
δ = 7.48 (d, J = 15.5 Hz, 1 H), 7.44 (d, J = 1.5 Hz, 1 H), 7.36 (d,
J = 5.3 Hz, 1 H), 7.21 (d, J = 3.4 Hz, 1 H), 7.10 (m, 2 H), 7.05
(dd, J = 3.9, 5.3 Hz, 1 H), 6.76 (d, J = 15.5 Hz, 1 H), 1.83 (s, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 161.4, 159.2, 140.7, 132.6,
131.3, 129.9, 129.2, 128.4, 128.3, 127.5, 126.5, 117.6, 105.5, 102.7,
25.2 ppm. IR (neat): ν = 1716, 1608, 1388, 1335, 1278, 1207,
˜
703 cm–1. HRMS (ESI-TOF): calcd. for C16H15O3S2 [M + H]+
319.0463; found 319.0464.
tert-Butyl (E)-2-Cyano-3-{4-[(2E,4E)-3-hydroxy-2,5-di(thiophen-2-
yl)penta-2,4-dienamido]phenyl}acrylate (23): Dioxinone 12
(15.4 mg, 48.4 µmol, 1.00 equiv.) and amine 17 (35.4 mg, 145 µmol,
3.00 equiv.) in toluene (0.5 mL), after 12 h, and purification by sil-
ica gel column chromatography (0–2 % ethyl acetate in toluene)
gave 23 (22.3 mg, 44.2 µmol, 91 %) as a yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 14.6 (br. s, 1 H), 8.06 (s, 1 H), 7.94 (d, J
= 8.7 Hz, 2 H), 7.64 (dd, J = 5.3, 1.0 Hz, 1 H), 7.55 (d, J = 8.7 Hz,
2 H), 7.42 (br. s, 1 H), 7.29 (d, J = 5.3 Hz, 1 H), 7.22 (dd, J = 5.3,
3.4 Hz, 1 H), 7.15 (d, J = 3.4 Hz, 1 H), 7.11 (dd, J = 3.4, 1.0 Hz,
1 H), 7.01 (dd, J = 5.3, 3.4 Hz, 1 H), 6.28 (d, J = 15.5 Hz, 1 H),
1.57 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 169.4,
161.6, 152.9, 141.4, 141.0, 134.2, 132.3, 131.4, 130.8, 129.7, 129.2,
128.1, 128.0, 127.7, 127.4, 119.9, 119.1, 116.0, 102.8, 97.6, 83.5,
tert-Butyl (E)-2-{2,2-Dimethyl-4-oxo-6-[2-(thiophen-2-yl)vinyl]-4H-
1,3-dioxine-5-carboxamido}acetate (13): (E)-5-Iodo-2,2-dimethyl-6-
[2-(thiophen-2-yl)vinyl]-4H-1,3-dioxin-4-one
(9;
45.0 mg,
0.124 mmol, 1.00 equiv.) and glycine tert-butyl ester hydrochloride
(11; 62.4 mg, 0.594 mmol, 3.00 equiv.) were suspended in DMF
(1 mL) in
a glass vessel. Pd(OAc)2 (2.8 mg, 0.012 mmol,
0.10 equiv.), [tBu3PH]BF4 (7.2 mg, 0.025 mmol, 0.20 equiv.), and
DBU (55.6 μL, 0.594 mmol, 3.00 equiv.) were added under Ar. The
vessel was placed in an autoclave, which was purged with CO three
times before pressure (15 atm) was applied. The mixture was stirred
at 80 °C for 24 h, then it was poured into HCl (1 m). The aqueous
layer was extracted with ethyl acetate. The combined organic layers
were washed with saturated aqueous NaHCO3 and brine, dried
with MgSO4, and filtered. The solvent was removed, and the resi-
due was purified by column chromatography on silica gel (0–25%
ethyl acetate in hexane) to give tert-butyl (E)-2-{2,2-dimethyl-4-
oxo-6-[2-(thiophen-2-yl)vinyl]-4H-1,3-dioxine-5-
27.9 ppm. IR (neat): ν = 3389, 2979, 2221, 1718, 1618, 1575, 1504,
˜
1416, 1285, 1155, 838, 703 cm–1. HRMS (ESI-TOF): calcd. for
C27H25N2O4S2 [M + H]+ 505.1256; found 505.1273.
tert-Butyl 4-[(2E,4E)-3-Hydroxy-2,5-di(thiophen-2-yl)penta-2,4-di-
enamido]benzoate (24): Dioxinone 12 (14.6 mg, 45.9 µmol,
1.00 equiv.) and amine 18 (26.6 mg, 138 µmol, 3.00 equiv.) in tolu-
ene (0.5 mL), after 24 h, and purification by silica gel column
chromatography (0–8% ethyl acetate in toluene) gave 24 (14.7 mg,
carboxamido}acetate (13; 40.1 mg, 0.102 mmol, 82%) as a pale yel-
1
low solid. H NMR (400 MHz, CDCl3): δ = 9.12 (br. s, 1 H), 8.03
(d, J = 15.5 Hz, 1 H), 7.66 (d, J = 15.9 Hz, 1 H), 7.45 (d, J =
5.3 Hz, 1 H), 7.34 (d, J = 3.4 Hz, 1 H), 7.08 (dd, J = 5.3, 3.4 Hz,
1 H), 4.08 (d, J = 5.3 Hz, 2 H), 1.79 (s, 6 H), 1.50 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.8, 168.7, 163.3, 162.6, 140.7,
134.9, 131.3, 129.9, 128.3, 118.7, 105.4, 99.3, 81.9, 42.2, 28.0,
1
38.1 µmol, 83%) as a yellow solid. H NMR (400 MHz, CDCl3): δ
= 14.7 (br. s, 1 H), 7.93 (d, J = 8.7 Hz, 2 H), 7.64 (d, J = 15.5 Hz,
1 H), 7.56 (dd, J = 5.3, 1.4 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 2 H),
7.35 (br. s, 1 H), 7.28 (d, J = 5.3 Hz, 1 H), 7.21 (dd, J = 5.3, 3.9 Hz,
1 H), 7.14 (d, J = 3.4 Hz, 1 H), 7.11 (dd, J = 3.4, 1.0 Hz, 1 H),
7.00 (dd, J = 5.3, 3.4 Hz, 1 H), 6.29 (d, J = 15.5 Hz, 1 H), 1.58 (s,
9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 169.0, 165.2,
141.0, 140.8, 134.5, 131.4, 130.5, 129.5, 129.1, 128.2, 128.0 (ϫ2),
25.0 ppm. IR (neat): ν = 3340, 2980, 2939, 1740, 1705, 1647, 1603,
˜
1547, 1372, 1352, 1276, 1228, 1156 cm–1. HRMS (ESI-TOF): calcd.
for C19H24NO6S [M + H]+ 394.1324; found 394.1326.
tert-Butyl 2-[(2E,4E)-3-Hydroxy-2,5-di(thiophen-2-yl)penta-2,4-di-
enamido]acetate (16): Glycine tert-butyl ester hydrochloride (11;
99.5 mg, 0.594 mmol, 10.0 equiv.) was added to a solution of (E)-
2,2-dimethyl-5-(thiophen-2-yl)-6-[2-(thiophen-2-yl)vinyl]-4H-1,3-di-
oxin-4-one (12; 18.9 mg, 0.059 mmol, 1.00 equiv.) in toluene
(0.600 mL) at room temperature in a sealed tube. The mixture was
stirred at reflux for 15 h, then it was poured into HCl (1 m). The
aqueous layer was extracted with ethyl acetate. The combined or-
ganic layers were washed with saturated aqueous NaHCO3 and
brine, dried with MgSO4, and filtered. The solvent was removed,
and the residue was purified by column chromatography on silica
gel (0–9% ethyl acetate in hexane) to give tert-butyl 2-[(2E,4E)-3-
hydroxy-2,5-di(thiophen-2-yl)penta-2,4-dienamido]acetate (16;
18.5 mg, 0.047 mmol, 80 %) as a pale yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 14.7 (br. s, 1 H), 7.57 (d, J = 15.5 Hz, 1
H), 7.48 (dd, J = 5.3, 1.0 Hz, 1 H), 7.25 (d, J = 5.3 Hz, 1 H), 7.14
(dd, J = 5.3, 3.4 Hz, 1 H) 7.11 (d, J = 3.9 Hz, 1 H), 7.04 (dd, J =
3.4, 1.0 Hz, 1 H), 6.99 (dd, J = 5.3, 3.9 Hz, 1 H), 6.30 (d, J =
15.5 Hz, 1 H), 6.02 (t, J = 4.8 Hz, 1 H), 3.96 (d, J = 5.3 Hz, 2 H),
127.7, 127.6, 119.2, 119.1, 97.7, 80.9, 28.2 ppm. IR (neat): ν = 3392,
˜
2977, 1707, 1621, 1592, 1520, 1408, 1294, 1237, 1163, 1114,
703 cm–1. HRMS (ESI-TOF): calcd. for C24H24NO4S2 [M + H]+
454.1147; found 454.1148.
(2E,4E)-N-(4-Cyanophenyl)-3-hydroxy-2,5-di(thiophen-2-yl)penta-
2,4-dienamide (25): Dioxinone 12 (13.7 mg, 43.0 µmol, 1.00 equiv.)
and amine 19 (15.2 mg, 129 µmol, 3.00 equiv.) in toluene (0.5 mL),
after 6 h, and purification by silica gel column chromatography (0–
15% ethyl acetate in toluene), gave 25 (14.7 mg, 38.8 µmol, 90%)
1
as a yellow solid. H NMR (400 MHz, CDCl3): δ = 14.5 (br. s, 1
H), 7.65 (d, J = 15.5 Hz, 1 H), 7.59 (d, J = 8.7 Hz, 2 H), 7.57 (dd,
J = 5.3, 1.0 Hz, 1 H), 7.54 (d, J = 8.7 Hz, 2 H), 7.36 (br. s, 1 H),
7.29 (d, J = 4.8 Hz, 1 H), 7.21 (dd, J = 5.3, 3.4 Hz, 1 H), 7.15 (d,
J = 3.4 Hz, 1 H), 7.11 (dd, J = 3.4, 1.0 Hz, 1 H), 7.01 (dd, J = 5.3,
3.4 Hz, 1 H), 6.28 (d, J = 15.5 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.5, 169.6, 141.2, 140.9, 134.1, 133.1, 131.5, 131.0,
129.8, 129.3, 128.1 (2 ϫ), 127.8, 119.9, 118.9, 118.7, 107.3,
97.4 ppm. IR (neat): ν = 3386, 2225, 1616, 1586, 1517, 1503, 1409,
˜
4858
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Eur. J. Org. Chem. 2014, 4854–4860