Journal of Agricultural and Food Chemistry
Article
10.02 (d, J = 0.9 Hz, 1H), 7.61 (d, J = 4.9 Hz, 1H), 6.99 (d, J = 4.9 Hz,
1H), 2.94 (t, J = 7.7 Hz, 2H), 1.55−1.74 (m, 2H), 1.17−1.42 (m,
14H), 0.86 (t, J = 6.8 Hz, 3H); EIMS (70 eV) m/z: 252 (19, M+), 126
(100), 139 (84), 97 (40), 125 (36), 41 (24), 113 (21), 43 (17), 98
(16), 128 (13).
addition of hexanes (10 mL). The reaction solution was warmed to
room temperature, and 3-bromo-2-methylprop-1-ene (3.0 g, 22.2
mmol) was added. After it was stirred at room temperature overnight,
the reaction was quenched with water (100 mL) and extracted with
ether (50 mL). The organic layer was concentrated, and the resultant
liquid was dissolved in acetone (40 mL) and water (10 mL). To this
solution was added TFA (1 mL), and the mixture stirred at room
temperature for 3 h. After evaporation of the solvent, the residue was
purified by chromatography on silica gel to provide 19 (0.2 g, 8% yield,
purity GC−MS: 95%): 1H NMR (CDCl3, 500 MHz) δ 10.04 (s, 1H),
7.66 (d, J = 5.0 Hz, 1H), 7.00 (d, J = 5.0 Hz, 1H), 4.87 (s, 1H), 4.70
(s, 1H), 3.67 (s, 2H), 1.75 (s, 3H); EIMS (70 eV) m/z: 166 (2, M+),
151 (100), 97 (13), 123 (13), 96 (10), 45 (10), 152 (10), 134 (10),
149 (10), 125 (9).
Synthesis of 3-Cyclohexyl-2-thiophenecarbaldehyde 18. Synthe-
sized similarly to 7 from 3-bromothiophene and cyclohexylmagnesium
1
chloride in 64% yield (purity GC−MS: 52%): H NMR (CDCl3, 400
MHz) δ 10.10 (s, 1H), 7.64 (d, J = 5.0 Hz, 1H), 7.10 (d, J = 5.0 Hz,
1H), 3.22−3.34 (m, 1H), 1.71−2.06 (m, 5H), 1.21−1.60 (m, 5H);
EIMS (70 eV) m/z: 194 (100, M+), 148 (79), 137 (69), 126 (63), 97
(57), 147 (42), 125 (41), 151 (38), 39 (33), 109 (31).
Synthesis of 3-(2-Methylpropyl)-2-thiophenecarbaldehyde 12.
Synthesized similarly to 7 from 3-bromothiophene and 2-methyl-
1
Synthesis of 4-Butyl-2-thiophenecarbaldehyde 23. A mixture of
4-bromo-2-thiophenecarbaldehyde (6.3 g, 33 mmol), 1-butaneboronic
acid (5.0 g, 49 mmol), palladium(II) acetate (0.1 g, 0.6 mmol), 2-
dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (0.6 g,
1.3 mmol), and anhydrous potassium carbonate (13.6 g, 98 mmol) in
toluene/water (9:1 by weight, 150 mL) was stirred and heated in a
sealed reactor at 150 °C for 6 h. After it was cooled down to room
temperature, the reaction mixture was diluted with ethyl acetate (100
mL). The organic layer was separated and washed twice with brine and
dried over MgSO4. After evaporation of the solvent, the residue was
purified by Kugelrohr distillation at 140−150 °C/1.1 mmHg to afford
propylmagnesium bromide in 27% yield (purity GC−MS: 60%): H
NMR (CDCl3, 500 MHz) δ 10.01 (d, J = 0.9 Hz, 1H), 7.63 (dd, J =
5.0, 0.9 Hz, 1H), 6.97 (d, J = 5.0 Hz, 1H), 2.83 (d, J = 6.9 Hz, 2H),
1.90−1.98 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H); EIMS (70 eV) m/z: 168
(50, M+), 125 (100), 126 (56), 153 (32), 97 (31), 135 (28), 53 (19),
45 (16), 43 (16), 41 (16).
Synthesis of 3-(3-Methylbutyl)-2-thiophenecarbaldehyde 13.
Synthesized similarly to 7 from 3-bromothiophene and 3-methyl-
1
butylmagnesium bromide in 64% yield (purity GC−MS: 75%): H
NMR (CDCl3, 500 MHz) δ 10.01−10.09 (m, 1H), 7.63 (dd, J = 5.0
Hz, 1H), 7.00 (d, J = 5.0 Hz, 1H), 2.92−3.01 (m, 2H), 1.49−1.66 (m,
3H), 0.95 (d, J = 6.3 Hz, 6H); EIMS (70 eV) m/z: 182 (22, M+), 139
(100), 126 (49), 125 (34), 97 (26), 45 (14), 53 (13), 39 (12), 41 (11),
98 (9).
1
23 (4.5 g, 82% yield, purity GC−MS: 87%): H NMR (CDCl3, 500
MHz) δ 9.86 δ (d, J = 1.3 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.34−
7.38 (m, 1H), 2.64 (t, J = 7.7 Hz, 2H), 1.57−1.68 (m, 2H), 1.28−1.48
(m, 2H), 0.93 (t, J = 7.3 Hz, 3H); EIMS (70 eV) m/z: 168 (33, M+),
126 (100), 125 (97), 97 (70), 53 (13), 45 (12), 77 (11), 127 (11), 69
(10), 111 (9).
Synthesis of 3-Cyclopropyl-2-thiophenecarbaldehyde 16. Synthe-
sized similarly to 7 from 3-bromothiophene and cyclopropylmagne-
sium bromide in 49% yield (purity GC−MS: 98%): 1H NMR (CDCl3,
400 MHz) δ 10.21 (s, 1H), 7.60 (d, J = 5.0 Hz, 1H), 6.68 (d, J = 5.0
Hz, 1H), 2.45−2.56 (m, 1H), 1.11−1.24 (dd, J = 8.4, 1.8 Hz, 2H),
0.83−0.92 (m, 2H); EIMS (70 eV) m/z: 152 (22, M+), 124 (100), 137
(83), 45 (34), 123 (23), 39 (22), 109 (21), 97 (19), 151 (18), 96 (17).
Synthesis of 3-Cyclopentyl-2-thiophenecarbaldehyde 17. Synthe-
sized similarly to 7 from 3-bromothiophene and cyclopentylmagne-
sium bromide in 72% yield (purity GC−MS: 75%): 1H NMR (CDCl3,
400 MHz) δ 9.99 (s, 1H), 7.52 (d, J = 5.1 Hz, 1H), 6.97 (d, J = 5.1 Hz,
1H), 3.50−3.65 (m, 1H), 1.93−2.08 (m, 2H), 1.38−1.77 (m, 6H);
EIMS (70 eV) m/z: 180 (100, M+), 124 (88), 137 (52), 97 (47), 139
(45), 134 (38), 39 (36), 147 (35), 45 (33), 151 (33).
Synthesis of 3-(3-Methylbut-2-en-1-yl)-2-thiophenecarbaldehyde
14. A 500 mL, three-neck flask was charged with water (85.0 mL) and
toluene (85.0 mL). Anhydrous potassium carbonate (20.0 g, 145
mmol), 2-formyl-3-thiopheneboronic acid (9.0 g, 58 mmol), and 1-
bromo-3-methylbut-2-ene (7.2 g, 48 mmol) were added, along with
RhPhos (0.9 g, 2 mmol) and palladium(II) acetate (0.2 g, 1 mmol).
The reaction mixture was refluxed for 4 h. The organic layer was
separated, washed with water and brine, and dried over MgSO4 and
concentrated. The residue was purified by chromatography on silica
gel eluting with hexane/ethyl acetate (10:1) to afford 14 (0.6 g, 2%
yield, purity GC−MS: 90%): 1H NMR (CDCl3, 400 MHz) δ 10.07 (s,
1H), 7.64 (d, J = 5.0 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 5.25−5.39 (m,
1H), 3.68 (d, J = 7.2 Hz, 2H), 1.67−1.82 (m, 6H); EIMS (70 eV) m/
z: 180 (39, M+), 124 (100), 137 (90), 96 (41), 97 (20), 125 (19), 165
(14), 138 (12), 91 (8), 135 (7).
Synthesis of 4-Ethyl-2-thiophenecarbaldehyde 21. Synthesized
similarly to 23 from 4-bromo-2-thiophenecarbaldehyde and 1-
1
ethaneboronic acid in 85% yield (purity GC−MS: 99%): H NMR
(CDCl3, 500 MHz) δ 9.85 (d, J = 0.9 Hz, 1H), 7.61 (d, J = 1.6 Hz,
1H), 7.30−7.41 (m, 1H), 2.66 (q, J = 7.7 Hz, 2H), 1.25 (t, J = 7.6 Hz,
3H); EIMS (70 eV) m/z: 140 (73, M+), 125 (100), 139 (30), 45 (20),
111 (12), 97 (12), 39 (11), 53 (9), 126 (8), 141 (8).
Synthesis of 4-Propyl-2-thiophenecarbaldehyde 22. Synthesized
similarly to 23 from 4-bromo-2-thiophenecarbaldehyde and 1-
1
propaneboronic acid in 73% yield (purity GC−MS: 87%): H NMR
(CDCl3, 500 MHz) δ 9.87 (d, J = 1.3 Hz, 1H), 7.60 (d, J = 1.3 Hz,
1H), 7.36−7.38 (m, 1H), 2.62 (t, J = 7.6 Hz, 2H), 1.61−1.70 (m, 2H),
0.96 (t, J = 7.3 Hz, 3H); EIMS (70 eV) m/z: 154 (40, M+), 125 (100),
126 (24), 97 (12), 45 (10), 53 (7), 39 (6), 127 (6), 155 (4), 69 (3).
Synthesis of 4-Pentyl-2-thiophenecarbaldehyde 24. Synthesized
similarly to 23 from 4-bromo-2-thiophenecarbaldehyde and 1-
1
pentaneboronic acid in 68% yield (purity GC−MS: 91%): H NMR
(CDCl3, 400 MHz) δ 9.88 (d, J = 1.1 Hz, 1H), 7.62 (d, J = 1.3 Hz,
1H), 7.36−7.40 (m, 1H), 2.65 (t, J = 7.7 Hz, 2H), 1.59−1.71 (m, 2H),
1.25−1.41 (m, 4H), 0.91 (t, J = 6.3 Hz, 4H); EIMS (70 eV) m/z: 182
(33, M+), 126 (100), 125 (80), 97 (50), 45 (14), 53 (11), 127 (10), 39
(9), 111 (9), 41 (8).
Synthesis of 4-Hexyl-2-thiophenecarbaldehyde 25. Synthesized
similarly to 23 from 4-bromo-2-thiophenecarbaldehyde and 1-
1
hexaneboronic acid in 79% yield (purity GC−MS: 90%): H NMR
(CDCl3, 400 MHz) δ 9.89 (s, 1H), 7.62 (d, J = 0.9 Hz, 1H), 7.39 (s,
1H), 2.66 (t, J = 7.7 Hz, 2H), 1.59−1.78 (m, 2H), 1.26−1.46 (m, 6H),
0.91 (t, J = 6.9 Hz, 3H); EIMS (70 eV) m/z: 196 (21, M+), 126 (100),
125 (51), 97 (27), 127 (10), 45 (9), 41 (7), 53 (7), 111 (7), 39 (7).
Synthesis of 4-(2-Methylpropyl)-2-thiophenecarbaldehyde 26.
Synthesized similarly to 23 from 4-bromo-2-thiophenecarbaldehyde
and 1-(2-methylpropane)boronic acid in 98% yield (purity GC−MS:
Synthesis of 3-(4-Methylpent-3-en-1-yl)-2-thiophenecarbalde-
hyde 15. Synthesized similarly to 14 from 2-formyl-3-thiophenebor-
onic acid and 1-bromo-4-methylpent-3-ene in 3% yield (purity GC−
1
MS: 65%): H NMR (CDCl3, 400 MHz) δ 9.97 (s, 1H), 7.63 (d, J =
5.0 Hz, 1H), 7.02 (d, J = 4.9 Hz, 1H), 5.14 (t, J = 7.4 Hz, 1H), 2.99 (t,
J = 7.4 Hz, 2H), 2.34 (dt, J = 7.4, 7.4 Hz, 2H), 1.67 (s, 3H), 1.45 (s,
3H); EIMS (70 eV) m/z: 194 (11, M+), 126 (100), 69 (68), 125 (43),
41 (38), 97 (15), 53 (14), 136 (12), 39 (10), 151 (9).
Synthesis of 3-(2-Methyl-allyl)-2-thiophenecarbaldehyde 19. To
a solution of 3-bromothiophene (5.22 g, 22 mmol) in hexane (30 mL)
was added n-butyllithium (2.4 M solution in hexanes, 9.3 mL, 22.4
mmol) dropwise at −40 °C under N2. After addition of THF (3 mL),
the reaction mixture was stirred at −40 °C for 0.5 h, followed by
1
90%): H NMR (CDCl3, 500 MHz) δ 9.87 (d, J = 1.3 Hz, 1H), 7.57
(d, J = 1.6 Hz, 1H), 7.33−7.37 (m, 1H), 2.51 (d, J = 7.3 Hz, 2H),
1.83−1.90 (m, 1H), 0.91 (d, J = 6.6 Hz, 6H); EIMS (70 eV) m/z: 168
(46, M+), 125 (100), 126 (77), 97 (36), 43 (16), 45 (15), 39 (11), 53
(11), 41 (11), 127 (11).
Synthesis of 4-(3-Methylbut-2-en-1-yl)-2-thiophenecarbaldehyde
27. A stirred mixture of (5-formylthiophen-3-yl)boronic acid (1.0 g,
D
J. Agric. Food Chem. XXXX, XXX, XXX−XXX