P. Langer et al.
FULL PAPER
(m, J7a,7b = 16.0 Hz, J = 7.4 Hz, 2 H, 7a-H, 7b-H), 1.39 (t, J =
2
3
3
1
less syrup (137 mg, 20%); Rf = 0.75 (n-heptane/EtOAc = 1:1). H
7.2 Hz, 3 H, OCH2CH3), 1.09 (t, J = 7.4 Hz, 3 H, 8-H) ppm. 13C NMR (300 MHz, CDCl3): δ = 8.49 (s, 1 H, OH), 7.16 (s, 1 H, 4-
3
NMR (76 MHz, CDCl3): δ = 177.6 (C=O), 170.9 (C-2), 139.0 (C- H), 5.85 (ddd, 3J = 6.8 Hz, 3J = 10.2 Hz, 1 H, HC=), 4.95–5.03
1
3
1), 126.4 (q, JC,F = 290.0 Hz, CF3), 119.5 (C-4), 96.1 (C-5), 74.0
(m, 2 H, H2C=), 3.92 (s, 3 H, OCH3), 2.74 (dd, J = 7.2 Hz, 2 H,
(q, JC,F = 30.0 Hz, C-6), 62.2 (OCH2CH3), 31.8 (C-3), 22.4 (C-7), ArCH2), 2.71 (dd, 5JH,F = 1.9 Hz, 3J = 7.4 Hz, 2 H, CH2CH3), 2.37
2
14.2 (OCH2CH3), 13.0 (C-8) ppm. 19F NMR (235 MHz, CDCl3):
(dd, 3J = 7.2 Hz, 2 H, ArCH2CH2), 1.22 (t, 3J = 7.4 Hz, 3 H,
CH2CH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 170.3 (C=O),
153.6 (C-2), 137.8 (H2C=), 135.8 (C-5), 135.7 (C-4), 124.6 (q, 2JC,F
δ = –79.9 (CF ) ppm. IR (Nujol): ν = 3529, 3353 (OH), 1689 cm–1
˜
3
(C=O). MS (EI, 70 eV): m/z (%) = 262 (17) [M+ – H2O], 216 (100)
[M+ – H2O – EtOH]. C12H15F3O4 (280.24): calcd. C 51.43, H 4.06;
found C 50.97, H 4.12.
1
= 29.6 Hz, C-6), 124.3 (q, JC,F = 275.9 Hz, CF3), 123.1 (C-3),
115.5 (HC=), 114.4 (C-1), 53.1 (OCH3), 33.2, 29.8 (CH2), 26.8
(CH2CH3), 16.2 (CH2CH3) ppm. 19F NMR (235 MHz, CDCl3): δ
Methyl 5-Ethyl-6-(trifluoromethyl)salicylate (4g): Following the ge-
neral procedure, 2c (750 mg, 3.8 mmol), 3d (2.00 g, 7.7 mmol) and
TiCl4 (0.42 mL, 3.8 mmol) yielded 4g as a colourless solid (670 mg,
= –53.9 (CF ) ppm. IR (neat): ν = 3420 (OH), 1716 cm–1 (C=O).
˜
3
MS (EI, 70 eV): m/z (%) = 302 (25) [M+], 270 (22) [M+ – CH3OH].
HRMS (EI): calcd. for C15H17F3O3 302.11243; found 302.112124
[M+].
71%); m.p. 84 °C; Rf = 0.45 (n-heptane/EtOAc = 2:3). 1H NMR
3
(250 MHz, CDCl3): δ = 8.14 (br. s, 1 H, OH), 7.32 (d, J3,4
=
3
8.5 Hz, 1 H, 3-H), 7.09 (d, J3,4 = 8.5 Hz, 1 H, 4-H), 3.93 (s, 3 H,
Methyl 3-(6-Chlorohexyl)-5-ethyl-6-(trifluoromethyl)salicylate (4k):
Following the general procedure, 2c (388 mg, 1.98 mmol), 3h
(1.50 g, 3.96 mmol) and TiCl4 (0.22 mL, 1.98 mmol) yielded 4k as
a colourless syrup (636 mg, 88%); Rf = 0.74 (n-heptane/EtOAc =
OCH3), 2.75 (dq, 3J = 7.3 Hz, 5JH,F = 2.4 Hz, 2 H, CH2CH3), 1.23
3
(t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR (63 MHz, CDCl3):
δ = 169.6 (C=O), 155.2 (C-2), 136.5 (C-5), 135.4 (C-4), 127.2 (q,
2JC,F = 31.0 Hz, C-6), 124.1 (q, JC,F = 276.0 Hz, CF3), 120.8 (C-
1
1
1:1). H NMR (300 MHz, CDCl3): δ = 8.47 (s, 1 H, OH), 7.15 (s,
4
3
3), 115.2 (C-1), 53.1 (OCH3), 26.6 (q, JC,F = 2.9 Hz, CH2CH3),
1 H, 4-H), 3.92 (s, 3 H, OCH3), 3.53 (t, J = 7.5 Hz, 2 H, CH2Cl),
16.1 (CH2CH3) ppm. 19F NMR (235 MHz, CDCl3): δ = –54.4
3
3
2.71 (dq, JH,F = 2.3 Hz, J = 7.5 Hz, 2 H, CH2CH3), 2.65 (t, J =
7.4 Hz, 2 H, CH2(CH2)5Cl), 1.32–1.82 (m, 8 H, CH2(CH2)4CH2Cl),
1.22 (t, 3J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR (76 MHz,
CDCl3): δ = 170.2 (C=O), 153.5 (C-2), 135.8 (C-5), 135.5 (C-4),
(CF ) ppm. IR (Nujol): ν = 3663 (OH), 1710 (C=O) cm–1. MS (EI,
˜
3
70 eV): m/z (%) = 248 (27) [M+], 217 (29) [M+ – OCH3], 216 (100)
[M+ – HOCH3]. C11H11F3O3 (248.20): calcd. C 53.23, H 4.47;
found C 53.59, H 4.93.
2
1
124.7 (q, JC,F = 31.0 Hz, C-6), 124.3 (q, JC,F = 274.3 Hz, CF3),
114.3 (C-1), 53.1 (OCH3), 45.2 (CH2Cl), 32.6, 30.1, 29.1, 28.8, 27.1,
26.8 (CH2), 16.3 (CH2CH3). 19F NMR (235 MHz, CDCl3): δ =
2-Acetyl-4-ethyl-3-(trifluoromethyl)phenol (4h): Following the gene-
ral procedure, 2c (800 mg, 4.1 mmol), 3e (2.00 g, 8.2 mmol) and
TiCl4 (0.45 mL, 4.1 mmol) yielded 4h as a colourless solid (376 mg,
–53.8 (CF ) ppm. IR (neat): ν = 3420 (OH), 1748 (C=O) cm–1. MS
˜
3
(EI, 70 eV): m/z (%) = 368 (3) [M+, 37Cl], 366 (17) [M+, 35Cl], 334
(16) [M+ – CH3OH]. HRMS (EI): calcd. for C17H22ClF3O3
366.12041; found 366.120050 [M+].
40%); m.p. 83 °C; Rf = 0.4 (n-heptane/EtOAc = 1:1). 1H NMR
3
(250 MHz, CDCl3): δ = 7.78 (br. s, 1 H, OH), 7.14 (d, J5,6
8.2 Hz, 1 H, 6-H), 6.94 (d, J5,6 = 8.2 Hz, 1 H, 5-H), 2.70 (q, J =
=
3
3
3
7.6 Hz, 2 H, CH2CH3), 2.52 (s, 3 H, COCH3), 1.18 (t, J = 7.6 Hz,
Ethyl 5-Ethyl-3-heptyl-6-(trifluoromethyl)salicylate (4l): Following
the general procedure, 2c (410 mg, 2.09 mmol), 3i (1.50 g,
4.18 mmol) and TiCl4 (0.45 mL, 4.1 mmol) yielded 4l as a colour-
3 H, CH2CH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 206.0
3
(C=O), 151.2 (C-1), 135.8 (C-4), 133.3 (C-5), 126.8 (q, JC,F
=
=
2
1
2.8 Hz, C-2), 125.1 (q, JC,F = 30.0 Hz, C-3), 124.8 (q, JC,F
1
less syrup (387 mg, 53%); Rf = 0.75 (n-heptane/EtOAc = 1:1). H
275.6 Hz, CF3), 120.5 (C-6), 32.2 (q, 5JC,F = 2.8 Hz, COCH3), 25.8
NMR (250 MHz, CDCl3): δ = 8.43 (br. s, 1 H, OH), 7.15 (s, 1 H,
4
(q, JC,F = 2.0 Hz, CH2CH3), 16.2 (CH2CH3) ppm. 19F NMR
3
5
4-H), 3.92 (s, 3 H, OCH3), 2.71 (dq, J = 7.5 Hz, JH,F = 1.8 Hz,
(235 MHz, CDCl ): δ = –53.3 (CF ) ppm. IR (Nujol): ν = 3419
˜
3
3
3
2 H, CH2CH3), 2.63 (t, J = 7.9 Hz, 2 H, ArCH2), 1.54–1.65 (m,
(OH), 1702 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 232 (29) [M+],
217 (100) [M+ – CH2CH3]. HRMS (EI): calcd. for C11H11F3O2
232.0706; found 232.0707 [M+].
3J = 7.9 Hz, 2 H, ArCH2CH2), 1.24–1.39 (m, 8 H, Ar(CH2)2(CH2)
3
3
4CH3), 1.22 (t, J = 7.5 Hz, 3 H, CH2CH3), 0.88 (t, J = 7.3 Hz, 3
H, Ar(CH2)6CH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 170.3
2
(C=O), 153.2 (C-2), 135.5 (C-5), 135.5 (C-4), 124.7 (q, JC,F
=
Methyl 3-Butyl-5-ethyl-6-(trifluoromethyl)salicylate (4i): Following
the general procedure, 2c (465 mg, 2.37 mmol), 3f (1.50 g,
4.74 mmol) and TiCl4 (0.26 mL, 2.4 mmol) yielded 4i as a colour-
less syrup (555 mg, 77%); Rf = 0.65 (n-heptane/EtOAc = 1:1). H
NMR (300 MHz, CDCl3): δ = 8.43 (s, 1 H, OH), 7.16 (s, 1 H, 4-
1
30.9 Hz, C-6), 124.4 (q, JC,F = 274.2 Hz, CF3), 122.5 (C-3), 114.3
3
(q, JC,F = 2.5 Hz, C-1), 53.0 (OCH3), 31.9, 30.2, 29.3, 29.2, 26.7
(Ar(CH2)6CH3), 26.7 (q, 4JC,F = 3.4 Hz, CH2CH3), 22.8 (Ar(CH2)6-
1
CH3), 16.2 (CH2CH3), 14.2 (Ar(CH2)6CH3) ppm. 19F NMR
5
3
(235 MHz, CDCl ): δ = –53.8 (CF ) ppm. IR (neat): ν = 3415
˜
H), 3.92 (s, 3 H, OCH3), 2.72 (dq, JH,F = 1.7 Hz, J = 7.4 Hz, 2
H, CH2CH3), 2.65 (t, 3J = 7.1 Hz, 2 H, CH2(CH2)2CH3), 1.53–1.64
(m, 2 H, CH2CH2CH2CH3), 1.31–1.44 (m, 2 H, (CH2)2CH2CH3),
1.22 (t, 3J = 7.4, 3 H, CH2CH3), 0.94 (t, 3J = 7.4 Hz, 3 H, (CH2)3-
3
3
(OH), 1746 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 346 (31) [M+],
314 (32) [M+ – CH3OH], 285 (49) [M+ – HC(O)OCH3].
Methyl 3-Benzyl-5-ethyl-6-(trifluoromethyl)salicylate (4m): Follow-
ing the general procedure, 2c (420 mg, 2.14 mmol), 3j (1.50 g,
4.28 mmol) and TiCl4 (0.26 mL, 2.1 mmol) yielded 4m as a colour-
CH3) ppm. 13C NMR (76 MHz, CDCl3): δ = 170.3 (C=O), 153.5
2
(C-2), 135.8 (C-5), 135.5 (C-4), 135.1 (C-3), 124.6 (q, JC,F
=
=
1
3
31.0 Hz, C-6), 124.3 (q, JC,F = 275.0 Hz, CF3), 114.4 (q, JC,F
1
less syrup (175 mg, 24%); Rf = 0.65 (n-heptane/EtOAc = 1:1). H
3.5 Hz, C-1), 53.0 (OCH3), 31.5, 30.0 (CH2), 26.7 (CH2CH3), 22.7
NMR (250 MHz, CDCl3): δ = 8.36 (s, 1 H, OH), 7.15–7.44 (m, 5
(CH2), 16.2, 14.1 (CH3) ppm. 19F NMR (282 MHz, CDCl3): δ =
H, Ph), 7.03 (s, 1 H, 4-H), 3.91 (s, 2 H, CH2), 3.82 (s, 3 H, OCH3),
–53.8 ppm. IR (neat): ν = 3427 (OH), 1746 (C=O) cm–1. MS (EI,
˜
5
3
3
2.59 (dq, JH,F = 1.9 Hz, J = 7.5 Hz, 2 H, CH2CH3), 1.09 (t, J =
7.5 Hz, 3 H, CH3CH3) ppm. 13C NMR (76 MHz, CDCl3): δ =
170.1 (C=O), 153.4 (C-2), 141.5 (CPh), 136.1 (C-5), 134.8 (C-4),
133.4 (C-3), 129.0, 128.7, 126.6 (CHPh), 123.7 (q, 1JC,F = 273.0 Hz,
CF3), 114.8 (q, 3JC,F = 3.5 Hz, C-1), 53.1 (OCH3), 36.0 (CH2), 26.6
(CH2CH3), 16.2 (CH2CH3) ppm. 19F NMR (235 MHz, CDCl3): δ
70 eV): m/z (%) = 304 (31) [M+], 273 (18) [M+ – OCH3]. HRMS
(EI): calcd. for C15H19F3O3 304.1281; found 304.1275 [M+].
Methyl 3-(But-3-enyl)-5-ethyl-6-(trifluoromethyl)salicylate (4j): Fol-
lowing the general procedure, 2c (468 mg, 2.38 mmol), 3g (1.50 g,
4.77 mmol) and TiCl4 (0.26 mL, 2.4 mmol) yielded 4j as a colour-
498
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Eur. J. Org. Chem. 2008, 492–502