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the spectra were performed using NMR DEPT, HSQC and
4.4. Methyl 2-amino-3,3,3-trifluoro-2-[4-(4-
fluorobenzoylamino)-3,5-dimethylphenyl]propionate (9)
NOESY procedures. Mass-spectra were obtained on a Kratos
MS-30 instrument (EI, 70 eV). Elemental analyses were
performed on a Carlo Erba 1106 instrument.
Compound 6 (0.38 g, 1 mmol) was dissolved in a 20%
solution of ammonia in methanol (2 ml) and kept at 0–5 8C
until the yellow colour of the reaction mixture disappeared (for
5–10 min). Removal of the solvent under vacuum gave
compound 9 (0.40 g, 1 mmol, 100%) as a white solid: mp
168–169 8C. 1H NMR (DMSO-d6): d 2.24 (6H, s), 3.38 (2H, s),
3.80 (3H, s), 7.33 (2H, s), 7.42 (2H, m), 8.10 (2H, m), 9.87 (1H,
bs). 19F NMR (DMSO-d6): d À108.99 (m, 1F), À73.72 (s, 3F).
Anal. calculated for C19H18F4N2O3: C, 57.29; H, 4.55; N, 7.03.
Found: C, 57.45; H, 4.33; N, 7.29.
4.1. Methyl 3.3,3-trifluoro-2-[4-(4-fluorobenzylamino)-3,5-
dimethylphenyl]-2-hydroxypropionate (4)
A mixture of compound 3 (2.87 g, 10 mmol), toluene
(20 ml), and 4-fluorobenzoyl chloride (1.59 g, 10 mmol) was
refluxed until liberation of HCl stopped (for about 1.5 h). The
reaction mixture was chilled and filtered to separate the
precipitate, which was washed with benzene and hexane to give
compound 4 (3.2 g, 8 mmol, 91%), white solid: mp 163–
164 8C. 1H NMR (DMSO-d6): d 2.20 (6H, s), 3.80 (3H, s), 7.40
(2H, s), 7.50 (2H, m), 7.95 (1H, s), 8.15 (2H, m); 9.90 (1H, s).
19F NMR (DMSO-d6): d À108.72 (m, 1F), À75.12 (s, 3F).
Anal. calculated for C19H17F4NO4: C, 57.15; H, 4.29; N, 3.51.
Found: C, 57.25; H, 4.11; N, 3.35.
4.5. Methyl 3,3,3-trifluoro-2-[4-(4-fluorobenzoylamino)-
3,5-dimethylphenyl]-2-phenylaminopropionate (11)
Aniline (0.10 g, 1.1 mmol) was added to a solution of
compound 6 (0.38 g, 1 mmol) in CCl4 (2 ml) and kept at
ambient temperature for 1 h. The crystalline precipitate that
formed was filtered off, washed with hexane and dried under
vacuum to give compound 11 (0.40 g, 0.84 mmol, 84%), white
4.2. Methyl 2-chloro-3.3,3-trifluoro-2-[4-(4-
fluorobenzylamino)-3,5-dimethylphenyl]-2-propionate (5)
1
solid: mp 102–103 8C. H NMR (DMSO-d6): d 2.28 (6H, s),
A mixture of compound 4 (2.0 g, 5 mmol), thionyl chloride
(2.4 g, 20 mmol), and 3 drops of pyridine was refluxed until
liberation of HCl stopped (for about 1 h). An excess of SOCl2
was removed under vacuum, crystallization of the residue gave
compound 5 (1.7 g, 4.1 mmol) as a white solid, mp 211–
212 8C. Yield 81.3%. 1H NMR (DMSO-d6): d 2.21 (6H, s), 3.90
(3H, s), 7.30 (2H, s), 7.41 (2H, m), 7.95 (1H, s), 8.10 (2H, m),
9.92 (1H, s). 19F NMR (DMSO-d6): d À108.27 (m, 1F), À71.22
(s, 3F). Anal. calculated for C19H16ClF4NO3: C, 54.62; H, 3.86;
N, 3.35. Found: C, 54.25; H, 3.53; N, 3.71.
3.38 (2H, s), 3.79 (3H, s), 5.19 (2H, s), 6.52 (2H, d,
J1 = 8.0 Hz), 6.74 (1H, t, J1 = 7.0 Hz), 7.04 (1H, t, J1 = 7.3 Hz),
7.16 (2H, m), 7.35 (2H, s), 7.40 (1H, bs), 7.90 (2H, m). 19F
NMR (CDCl3): d À107.00 (m, 1F), À68.60 (s, 3F). Anal.
calculated for C25H22F4N2O3: C, 63.29; H, 4.67; N, 5.90.
Found: C, 63.45; H, 4.43; N, 5.79.
4.6. Methyl 2-(4-amino-3,5-dimethylphenyl)-3,3,3-
trifluoro-2-[4-(4-fluorobenzoylamino)-3,5-dimethylphenyl-
propioate (12)
4.3. Methyl 3,3,3-trifluoro-2-[4-(4-fluorobenzylamino)-3,5-
dimethylcyclohexa-2,5-dienylidene]propionate (6) (Fig. 2)
2,6-Dimethylaniline (0.13 g, 1.1 mmol) was added to a
solution of compound 6 (0.38 g, 1 mmol) in CCl4 (1.5 ml) and
kept at ambient temperature for 1 h. The crystalline precipitate
that formed was filtered off, washed with hexane and dried
under vacuum to give compound 12 (0.40 g, 0.80 mmol, 80%),
A mixture of compound 5 (1.25 g, 3 mmol), KOH (0.56 g,
10 mmol) in adhydrous diethyl ether (30 ml) was stirred by a
magnetic stirrer at 20 8C for 1.5 h and filtered to separate the
precipitate of inorganic salts. The filtrate was evaporated under
vacuum, the resulting crude product was purified by column
chromatography on Merck silica gel 60 (230–400 mesh ASTM),
eluent CHCl3–CCl4 (1:2) to give pure compound 6 (0.92 g,
2.42 mmol) as a yellow solid: mp 100–101 8C (hexane). Yield
81%. 1H NMR (CDCl3-d6): d 2.07 (s, 3H), 2.12 (d, 4J = 1.1 Hz,
3H), 3.98 (s, 3H), 6.94 (bs, 1H), 7.16 (m, 2H), 7.17 (bs, 1H), 7.87
(m, 2H). 13C NMR (150.93 MHz) d 20.0 (10–C), 20.2 (14-C),
1
white solid: mp 218–219 8C. H NMR (CDCl3-d6): d 2.16 (s,
6H), 2.24 (s, 6H), 3.83 (s, 3H), 3.84 (bs, 2H), 6.84 (s, 2H), 7.04
(s, 2H), 7.17 (m, 2H), 7.33 (bs, 1H), 7.91 (m, 2H). 19F NMR
(CDCl3): d À107.16 (m, 1F), À62.41 (s, 3F). Anal. calculated
for C27H26F4N2O3: C, 64.54; H, 5.22; N, 5.57. Found: C, 64.43;
H, 5.41; N, 5.74.
4.7. Methyl 2-ethoxy-3,3,3-trifluoro-2-[4-(4-
fluorobenzoylamino)-3,5-dimethylphenyl propionate (14)
2
1
53.3 (24-C), 115.9 (d, JC-F = 22 Hz, 17(19)-C), 121.8 (q, JC-
F = 273 Hz, 21-C), 125.2 (q, 2JC-F = 33 Hz, 11-C), 128.0 (q, 4JC-
F = 2 Hz, 5-C), 129.4 (d, 4JC-F = 3 Hz, 15-C), 130.1 (3-C), 131.3
(d, 3JC-F = 9 Hz, 16(20)-C), 136.7 (q, 3JC-F = 3 Hz, 4-C), 139.4
Compound 6 (0.38 g, 1 mmol) was dissolved in a freshly
prepared solution of NaH (0.024 g, 1 mmol) in anhydrous
ethanol (4 ml) and stirred for 2 min at ambient temperature.
Then acetic acid (0.1 g) and water (6 ml) were added to the
reaction mixture. The precipitate that formed was filtered off,
washed with water, and dried under vacuum to give compound
14 (0.42 g, 0.98 mmol, 98%), white solid: mp 208–209 8C. 1H
NMR (DMSO-d6): d 1.26 (bt, 3H, J = 7.1 Hz), 2.22 (s, 6H,),
4
(6-C), 140.0 (2-C), 154.6 (1-C), 163.6 (q, JC-F = 3 Hz, 12-C),
165.7 (d, 1JC-F = 253 Hz, 18-C), 176.0 (8-C). 19F NMR (CDCl3)
d: À105.30 (m, 1F); À54.05 (s, 3F). EIMS, m/z: 381[M]+. Anal.
calculated for C19H15F4NO3: C, 59.85; H, 3.96; N, 3.67. Found:
C, 59.65; H, 3.84; N, 3.59.