A. Cheguillaume et al. / Tetrahedron Letters 44 (2003) 2375–2377
2377
12. Katritzky, A. R.; Yannakopoulou, R.; Lue, P.; Rasala,
D.; Urogdi, L. J. Chem. Soc., Perkin Trans. 1 1989,
225–233. Compound 1 is commercially available (Hetero-
cyclic Compounds Catalog: RN 57684-32-9).
13. Katritzky, A. R.; Nichols, D. A.; Qi, M. Tetrahedron
Lett. 1998, 39, 7063–7066.
colorless oil (0.646 g, 81%). 1H NMR (200 MHz, D2O)
l=1.33 (t, 3H, J=7.2 Hz, CH3); 3.80 (t, 2H, J=15.6 Hz,
CH2CF2); 4.41 (q, 2H, J=7.2 Hz, CH2); 19F NMR (282
MHz, DMSO-d6) l=−73.48 (s, CF3CO2H); −107.75 (t,
J=16 Hz, CF2); 13C NMR (50 MHz, DMSO-d6) l=
40.34 (t, JCꢀF=21.1 Hz, CH2CF2); 112.58 (t, JCꢀF=250.8
Hz, CF2); 116.77 (q, JCꢀF=294.4 Hz, CF3); 158.97 (t,
14. Lindsay Smith, J. R.; Sadd, J. S. J. Chem. Soc., Perkin
Trans. 1 1975, 1181–1184.
JCꢀF=33 Hz, CF3CꢁO); 161.26 (t, JCꢀF=30.5 Hz,
15. Katritzky, A. R.; Yannakopoulou, K.; Kuzmierkiewicz,
W.; Aurreccoechea, J. M.; Palenik, G. J.; Koziol, A. E.;
Szczesniak, M. J. Chem. Soc., Perkin Trans. 1 1987,
2673–2679.
CF2CꢁO); MS (APCI, CH4-NO2): m/z=154.14 (M+1).
20. Aguilar, N.; Moyano, A.; Pericas, M. A.; Riera, A.
Synthesis 1998, 313–316.
21. Synthesis and characterization of 6: to a suspension of
PyBOP (0.437 g, 0.84 mmol) in THF (2 mL) was added
a solution of 2-(methoxycarbonyl)benzoic acid (0.144 g,
0.802 mmol) in THF (2 mL) and pyridine (0.094 mL,
0.090 g, 1.15 mmol). The mixture was stirred at rt for 45
min. 5 (0.204 g, 0.764 mmol) in THF (2 mL) was
introduced in one portion followed by a slow addition of
pyridine (0.467 mL, 0.453 g, 5.73 mmol). After stirring at
rt for 4 h, a catalytic amount of p-TsOH was added
before refluxing for 48 h. After cooling to rt, the solution
was poured on aqueous 5% NaHCO3 (10 mL) and
extracted with EtOAc (3×10 mL). The organic layer was
dried (MgSO4) and concentrated before purification by
flash chromatography on silica gel (hexane:EtOAc 70:30
(Rf=0.56)) to afford 6 as a white solid. Yield 48% (0.45
g); mp=89.5–90.5°C; 1H NMR (200 MHz, CDCl3) l=
1.35 (t, 3H, J=7.1 Hz, CH3); 4.32 (t, 2H, J=13 Hz,
CH2CF2); 4.34 (q, 2H, J=7.1 Hz, CH2); 7.74–7.93 (m,
4Harom.); 19F NMR (282 MHz, CDCl3/CFCl3) l=
−109.70 (t, JFꢀH=12.8 Hz, CH2CF2); 13C NMR (50
MHz, CDCl3) l=13.83 (CH3); 40.29 (t, JCꢀF=29.5 Hz,
CH2CF2); 63.54 (OCH2CH3); 112.10 (t, JCꢀF=253.8 Hz,
CF2); 123.80, 131.89 and 134.46 (Carom.); 162.63 (t,
16. Wang, Y.; Zhu, S. Synthesis 2002, 13, 1813–1818.
17. Synthesis and characterization of 3: to a suspension of
zinc dust (0.921 g, 14.2 mmol) in dry THF (10 mL),
stirred under argon atmosphere, was added chloro-
trimethylsilane (0.905 mL, 0.769 g, 7.09 mmol) followed,
10 min later, by ethyl bromodifluoroacetate (1 mL, 1.583
g, 4.57 mmol). After 10 min, 1 (2.35 g, 7.08 mmol) in
THF (5 mL) was added dropwise. After 3 h at rt, the
mixture was poured on aqueous 5% NaHCO3 (10 mL)
and filtered on Celite 545. The layers were separated and
the aqueous phase was extracted with EtOAc (3×10 mL).
The organic layers were combined and washed with 1N
HCl (20 mL), then dried over MgSO4. After evaporation
of the solvent, the residue was diluted in ether; the solid
formed was removed by filtration and ether was evapo-
rated. Distillation of the oil (pressure 3×10−3 mBar, tem-
perature=115–120°C) give 3 (2.21 g, 94%) as a colorless
1
oil. Rf=0.47 (EtOAc:hexane, 5:95). H NMR (200 MHz,
CDCl3) l=1.22 (t, 3H, J=7.2 Hz, CH3); 3.15 (t, 2H,
J=13.1 Hz, CH2CF2); 3.68 (s, 4H, CH2Ph); 4.18 (q, 2H,
J=7.2 Hz, CH2O); 7.24–7.35 (m, 10Harom.); 19F NMR
(282 MHz, CDCl3/CFCl3) l=−106.32 (t, JFꢀH=13.8 Hz,
CH2CF2); 13C NMR (50 MHz, CDCl3) l=13.73 (CH3);
53.81 (t, JCꢀF=26.1 Hz, CH2CF2); 58.47 (CH2); 62.53
(CH2); 116.16 (t, JCꢀF=251.4 Hz, CF2); 114.48, 129.26,
129.51, 159.67 (Carom.); 160.28 (t, JCꢀF=30.5 Hz, CꢁO);
HRMS (M+1) calcd for C19H21NO2F2=334.160545;
found: 334.161861.
JCꢀF=31.1 Hz, CF2CꢁO), 167.08 (s, 2×N-CꢁO); MS
(APCI, CH4-NO2): m/z=284.1 (M+1), 256.1, 238, 210.3.
22. Synthesis and characterization of 7: to a solution of 6
(0.172 g, 0.607 mmol) in acetonitrile (3 mL) was added
1N LiOH aqueous solution (3 mL). The mixture was
stirred for 3 h at rt. After evaporation of the solvent, the
residue was diluted with water (5 mL) and washed with
ether (10 mL). The aqueous phase was treated with 1N
HCl aqueous solution (until pH 1) and extracted with
EtOAc (3×10 mL). The organic layer was dried (MgSO4)
and concentrated to give 7 (0.21 g, 74%) as a hygroscopic
white solid. Mp=140–141.5°C; 1H NMR (200 MHz,
(CD3)2CO) l=4.09 (t, 2H, J=14.4 Hz, CH2CF2); 7.49–
7.94 (m, 4Harom.); 19F NMR (282 MHz, (CD3)2CO/
CFCl3) l=−109.719 (t, JFꢀH=14.9 Hz, CH2CF2); 13C
NMR (50 MHz, (CD3)2CO) l=42.89 (t, JCꢀF=28 Hz,
CH2CF2); 114.88 (t, JCꢀF=249.1 Hz, CF2); 128.92,
130.51, 130.94, 132.60, 137.19 and 139.16 (Carom.); 164.78
(t, JCꢀF=30.6 Hz, CꢁO), 167.90 and 170.53 (s, N-CꢁO);
MS (APCI, CH4-NO2): m/z=254.5 (M−1), 291.5, 146.2.
Anal. calcd for C11H7NO4F2·1.75H2O: C, 46.08; H, 3.69;
N, 4.88. Found: C, 46.46; H, 3.58; N, 5.03.
18. Synthesis and characterization of 4: compound 3 (2.07 g,
6.2 mmol) was dissolved in a solution of EtOH: 0.5N
HCl (1:1) (10 mL) and Pd(OH)2 (20 wt.% on carbon)
(0.217 g, 1.55 mmol) was added. After stirring for 36 h
under H2 atmosphere, the catalyst was removed by filtra-
tion on Celite 545. The mixture was diluted with ether (5
mL); the aqueous phase was isolated and evaporated to
give a colorless oil which precipitated in chloroform to
give the hydrochloride as a white solid (0.61 g, 65%).
Distilled water was added, the mixture was adsorbed on
cation-exchange resin (DOWEX 50X2 400) and the resin
was washed with water (until water came out neutral),
then with 1.5 M aqueous NH4OH to recover the b-amino
acid. Concentration of the aqueous solution afforded
quantitatively 4 as a white solid. (for analytical data, see
Ref. 11).
19. Synthesis and characterization of 5: to a solution of 3 (1
g, 3.02 mmol) in EtOH (4 mL) and trifluoroacetic acid
(0.28 mL, 3.62 mmol) was added Pd(OH)2 (20 wt.% on
carbon) (0.105 g, 0.151 mmol). After 36 h of stirring
under H2 atmosphere, the solution was filtered on Celite
545 and the solvent was evaporated to afford 5 as a
23. Josse, O.; Labar, D.; Marchand-Brynaert, J. Synthesis
1999, 404–406.
24. Doszczak, L.; Rachon, R. J. Chem. Soc., Perkin Trans. 1
2002, 1271–1279.