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G. Anquetin et al. / Tetrahedron 61 (2005) 8394–8404
4.5.2.2. 3-Ethyl-2,4,5-trifluoro-N-(2-hydroxy-1,1-
(0.09 mmol, 36%) of acid 10b as a white solid: RfZ0.70
(CH2Cl2/MeOH/H20 84/14/2 UV); 1H NMR (CDCl3) d 1.22
dimethyl-ethyl)-benzamide (11b). Hydrolysis of 5b
(418 mg, 1.62 mmol) when performed with 1 N HCl during
6 h at reflux and work-up as described above afforded acid
9b (94 mg, 0.46 mmol, 28%). Evaporation of the organic
phase after extraction with 1 N NaOH and chromatography
of the residue (9:1 to 3:2 hexane/AcOEt) led to the title
compound 11b (160 mg, 0.58 mmol, 36%) as a colorless
liquid: RfZ0.30 (7:3 hexane/AcOEt, UV); 1H NMR
3
and 1.24 (t, t, 3H, 3H, CH3CH2, JH–HZ7.5 Hz), 2.71 (bq,
3
2H, CH3CH2, JH–HZ7.5 Hz), 2.83 (qd, 2H, CH3CH2,
4
3JH–HZ7.5 Hz, JH–FZ2.2 Hz); 13C NMR (CDCl3) d 14.0
[CH3CH2 (R3)], 14.9 [CH3CH2 (R6)], 16.3 [CH3CH2 (R3)],
20.4 [CH3CH2 (R6)], 116.0 (m, C1), 119.6 (dd, C3, 2JC–F
Z
2
22.4, 17.8 Hz), 130.7 (d, C6, JC–FZ16.1 Hz), 145.7 (ddd,
1
2
4
C5, JC–FZ242.0 Hz, JC–FZ13.2 Hz, JC–FZ3.5 Hz),
3
1
2
(CDCl3) d 1.16 (t, 3H, CH3CH2, JH–3HZ7.5 Hz), 1.35 (s,
150.5 (dt, C4, JC–FZ253.0 Hz, JC–FZ3JC–FZ10.2 Hz),
1 3 4
6H, NCCH3), 2.68 (q, 2H, CH3CH2, JH–HZ7.5 Hz), 3.60
154.3 (ddd, C2, JC–FZ250.0 Hz, JC–FZ5.7 Hz, JC–F
Z
(s, 2H, OCH2), 4.59 (s, 1H, OH), 6.91 (d, 1H, NH, 5JH–F
Z
C
2.3 Hz), 169.5 (C]O); 19F NMR (CDCl3) d K121.3 (dd,
13.9 Hz), 7.60 (td, 1H, H6, 3JH–FZ4JH–FZ9.4, 7.8 Hz); 13
NMR (CDCl3) d 13.8 (CH3CH2), 16.4 (CH3CH2), 24.3
(NCCH3), 56.5 (CMe2), 70.0 (CH2OH), 116.1 (ddd, C6,
1F, F2, JF–FZ14.4 Hz, JF–FZ7.6 Hz), K135.6 (dd, 1F,
5
4
3 4
F4, JF–FZ21.3 Hz, JF–FZ7.6 Hz), K147.2 (dd, 1F, F5,
3JF–FZ21.3 Hz, 5JF–FZ14.4 Hz); ESI-MS (negative mode):
231.40 (MKH)K, 187.07 (M–H–CO2)K in agreement with
the mass calculated for MZC11H11F3O2 (232.18); high
resolution ESI-MS (negative mode): 231.0645 (MKH)K, in
agreement with the mass calculated for (MKH)KZ
C11H10F3O2 (231.0633).
2JC–FZ21.0 Hz, 3JC–FZ3.7, 1.8 Hz), 117.9 (dt, C1, 2JC–F
Z
Z
Z
3
2
14.3 Hz, JC–FZ4JC–FZ4.6 Hz), 122.1 (dd, C3, JC–F
1
2
25.8, s17.4 Hz), 147.1 (ddd, C5, JC–FZ246.3 Hz, JC–F
4
1
13.5 Hz, JC–FZ2.9 Hz), 150.6 (ddd, C4, JC–FZ254.0 Hz,
2JC–FZ14.3 Hz, JC–FZ9.9 Hz), 154.3 (ddd, C2, JC–F
Z
3
1
3
4
243.7 Hz, JC–FZ7.0 Hz, JC–FZ2.6 Hz), 162.2 (d, C]O,
3JC–FZ3.6 Hz); 19F NMR (CDCl3) d K121.1 (dd, 1F, F2,
4.5.2.5. Hydrolysis of 6a into 3,6-dimethyl-2,4,5-
trifluoro-benzoic acid (10a). A suspension of 6a in 12 N
HCl was stirred under reflux for 36 h. Work-up as described
for 10b led to 10a whose NMR data are identical to those
reported in literature.33
5JF–FZ16.5 Hz, JF–FZ8.9 Hz), K133.8 (dd, 1F, F4,
4
3JF–FZ22.0 Hz, JF–FZ8.9 Hz), K141.2 (dd, 1F, F5,
4
3JF–FZ22.0 Hz, JF–FZ16.5 Hz).
5
4.5.2.3. Hydrolysis of 6b into 3,6-diethyl-2,4,5-tri-
fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide
(12b). A suspension of 6b (270 mg, 0.95 mmol) in 6 mL of
6 N HCl was refluxed for 12 h. The aqueous phase was
extracted with CH2Cl2. The organic phase was then dried
(Na2SO4), filtrated, and concentrated leading to 208 mg
(0.69 mmol, 73%) of 12b as a white solid: RfZ0.65 (4:1
hexane/AcOEt, UV); mpZ125–127 8C; IR (KBr, cmK1):
3246 (NH), 3060 (OH), 1641 (C]O), 1563 (CNH), 1464
4.5.2.6. Hydrolysis of 6c into (2-amino-2-methyl-
propyl) 6-ethyl-2,4,5-trifluoro-3-methoxy-benzoate
(13c). A suspension of 6c (770 mg, 2.68 mmol) in 10 mL
of 1 N HCl was stirred under reflux for 6 h. After extraction
with CH2Cl2, the organic phase was dried (Na2SO4),
filtrated, and concentrated to give 556 mg (1.63 mmol,
61%) of 13c (as its HCl salt) as a white solid. The remaining
aqueous phase was made basic with NaOH aq solution and
was extracted by CH2Cl2, which, after work-up, gave
another crop of 305 mg (1.0 mmol, 37%) of 13c as its NH2
form: mpZ162–163 8C; IR (KBr, cmK1): 1706 (C]O),
1
(NH); H NMR (CDCl3) d 1.18 and 1.20 (t, t, 3H, 3H,
3
CH3CH2, JH–HZ7.5 Hz), 1.48 (s, 6H, NCCH3), 2.71
3
(bq, 4H, CH3CH2, JH–HZ7.5 Hz), 3.91 (s, 2H, CH2O),
5.78 (br s, 1H, NH); 13C NMR (CDCl3) d 14.0 [CH3CH2
(R3)], 15.1 [CH3CH2 (R6)], 16.2 [CH3CH2 (R3)], 20.2
[CH3CH2 (R6)], 25.2 (NCCH3), 51.0 (CH2O), 55.3
1
1469 and 1413 (CO); H NMR (CDCl3) d 1.13 (bt, 9H,
3
4
CH3), 2.65 (qd, 2H, CH3CH2, JH–HZ7.5 Hz, JH–F
Z
2
2.1 Hz), 3.95 (s, 3H, OCH3), 4.06 (s, 2H, OCH2); 13C NMR
(CDCl3) d 14.9 (CH3CH2), 19.9 (CH3CH2), 27.1 (NCCH3),
49.4 (CMe2), 62.1 (t, OCH3, 4JC–FZ3.5 Hz), 75.2 (OCH2),
(CMe2), 119.0 (dd, C3, JC–FZ23.2, 17.4 Hz), 121.0
2
3
(dt, C1, JC–FZ18.7 Hz, JC–FZ4JC–FZ2.9 Hz), 129.3
2
3
(dd, C6, JC–FZ15.5 Hz, JC–FZ4.2 Hz), 145.7 (ddd, C4,
1JC–FZ249.6 Hz, JC–FZ14.8 Hz, JC–FZ10.1 Hz), 149.2
2
3
2
3
117.1 (dt, C1, JC–FZ15.7 Hz, JC–FZ4JC–FZ4.0 Hz),
1
2
4
2
3
(ddd, C5, JC–FZ243.2 Hz, JC–FZ13.2 Hz, JC–F
Z
125.8 (dd, C6, JC–FZ16.1 Hz, JC–FZ2.2 Hz), 135.7
(ddd, C3, JC–FZ15.9, 11.3 Hz, JC–FZ2.4 Hz), 145.7
(ddd, C4, JC–FZ253.9 Hz, JC–FZ15.9 Hz, JC–F
6.0 Hz), 145.9 (ddd, C5, JC–FZ244.4 Hz, JC–F
1
3
2
3
3.7 Hz), 152.6 (ddd, C2, JC–FZ243.0 Hz, JC–FZ8.1 Hz,
4JC–FZ3.3 Hz), 163.6 (C]O); 19F NMR (CDCl3) d
1
2
3
Z
Z
Z
5
4
1
2
K125.7 (dd, 1F, F2, JF–FZ15.1 Hz, JF–FZ5.5 Hz),
K139.0 (dd, 1F, F4, JF–FZ21.3 Hz, JF–FZ5.5 Hz),
K147.7 (dd, 1F, F5, JF–FZ21.3 Hz, JH–FZ15.1 Hz);
ESI-MS (positive mode): 303.7 (M)C in agreement with
the mass calculated for MZC15H20F3NO2 (303.32).
3
4
4
1
11.0 Hz, JC–FZ3.6 Hz), 149.5 (dt, C2, JC–F
3
5
249.6 Hz, JC–FZ4JC–FZ4.0 Hz), 163.9 (dd, C]O,
3
3JC–FZ2.9 Hz, JC–FZ1.5 Hz); 19F NMR (CDCl3) d
4
5
4
K134.8 (dd, 1F, F2, JF–FZ12.4 Hz, JF–FZ6.9 Hz),
K145.1 (dd, 1F, F5, JF–FZ20.6 Hz, JF–FZ12.4 Hz),
K148.4 (dd, 1F, F4, JF–FZ20.6 Hz, JF–FZ6.9 Hz).
3
5
3
4
4.5.2.4. Hydrolysis of 12b into 3,6-diethyl-2,4,5-
trifluoro-benzoic acid (10b). A suspension of 76 mg
(0.25 mmol) of 12b in 5 mL of 12 N HCl was refluxed for
24 h. The reaction mixture was made basic with 10 N
NaOH, then washed with CH2Cl2 (recovery of 48 mg of
starting material 64%). The aqueous phase acidified with
12 N HCl was extracted with CH2Cl2. The organic phase
was then washed with water until neutrality, dried
(Na2SO4), filtrated, concentrated giving 21 mg
Compound 13c (as its HCl salt): 1H NMR (CDCl3) d 1.13 (t,
3
3H, CH3CH2, JH–HZ7.5 Hz), 1.46 (s, 6H, NCCH3), 2.65
(bq, 2H, CH3CH2, 3JH–HZ7.5 Hz), 3.98 (s, 3H, OCH3), 4.37
(s, 2H, OCH2); 19F NMR (CDCl3) d K133.0 (dd, 1F, F2,
4
5JF–FZ12.6 Hz, JF–FZ7.9 Hz), K145.0 (dd, 1F, F5,
5
3JF–FZ20.6 Hz, JF–FZ12.4 Hz), K147.4 (dd, 1F, F4,
4
3JF–FZ20.6 Hz, JF–FZ7.9 Hz).